Faculty Bibliography

Hippocampal neurons can display reliable and long-lasting sequences of transient firing patterns, even in the absence of changing external stimuli. We suggest that time-keeping is an important function of these sequences, and propose a network mechanism for their generation. We show that sequences of neuronal assemblies recorded from rat hippocampal CA1 pyramidal cells can reliably predict elapsed time (15-20 s) during wheel running with a precision of 0.5 s. In addition, we demonstrate the generation of multiple reliable, long-lasting sequences in a recurrent network model. These sequences are generated in the presence of noisy, unstructured inputs to the network, mimicking stationary sensory input. Identical initial conditions generate similar sequences, whereas different initial conditions give rise to distinct sequences. The key ingredients responsible for sequence generation in the model are threshold-adaptation and a Mexican-hat-like pattern of connectivity among pyramidal cells. This pattern may arise from recurrent systems such as the hippocampal CA3 region or the entorhinal cortex. We hypothesize that mechanisms that evolved for spatial navigation also support tracking of elapsed time in behaviorally relevant contexts

Considerable evidence indicates that the general blockade of protein synthesis prevents both the initial consolidation and the postretrieval reconsolidation of long-term memories. These findings come largely from studies of drugs that block ribosomal function, so as to globally interfere with both cap-dependent and -independent forms of translation. Here we show that intra-amygdala microinfusions of 4EGI-1, a small molecule inhibitor of cap-dependent translation that selectively disrupts the interaction between eukaryotic initiation factors (eIF) 4E and 4G, attenuates fear memory consolidation but not reconsolidation. Using a combination of behavioral and biochemical techniques, we provide both in vitro and in vivo evidence that the eIF4E-eIF4G complex is more stringently required for plasticity induced by initial learning than for that triggered by reactivation of an existing memory

The purpose of this study was to develop a unified model capable of explaining the mechanisms of interaction of ultrasound and biological tissue at both the diagnostic nonthermal, noncavitational (<100 mW . cm(-2)) and therapeutic, potentially cavitational (>100 mW . cm(-2)) spatial peak temporal average intensity levels. The cellular-level model (termed "bilayer sonophore") combines the physics of bubble dynamics with cell biomechanics to determine the dynamic behavior of the two lipid bilayer membrane leaflets. The existence of such a unified model could potentially pave the way to a number of controlled ultrasound-assisted applications, including CNS modulation and blood-brain barrier permeabilization. The model predicts that the cellular membrane is intrinsically capable of absorbing mechanical energy from the ultrasound field and transforming it into expansions and contractions of the intramembrane space. It further predicts that the maximum area strain is proportional to the acoustic pressure amplitude and inversely proportional to the square root of the frequency (epsilon A,max proportional, variant P(A)(0.8f - 0.5) and is intensified by proximity to free surfaces, the presence of nearby microbubbles in free medium, and the flexibility of the surrounding tissue. Model predictions were experimentally supported using transmission electron microscopy (TEM) of multilayered live-cell goldfish epidermis exposed in vivo to continuous wave (CW) ultrasound at cavitational (1 MHz) and noncavitational (3 MHz) conditions. Our results support the hypothesis that ultrasonically induced bilayer membrane motion, which does not require preexistence of air voids in the tissue, may account for a variety of bioeffects and could elucidate mechanisms of ultrasound interaction with biological tissue that are currently not fully understood.

The largest subunit of the mammalian SWI/SNF-A or BAF (BRG1-associated factor) chromatin-remodelling complex is encoded by two related cDNAs hOsa1/BAF250a and hOsa2/BAF250b that are unique to the BAF complex and absent in the related PBAF (Polybromo BAF). hOsa/BAF250 has been shown to interact with transcriptional activators and bind to DNA suggesting that it acts to target the remodelling complex to chromatin. To better understand the functions of hOsa2, we established inducible stable HeLa cell lines over-expressing FLAG-hOsa2 or a derivative lacking the ARID (AT-rich interactive domain) DNA-binding domain. Immunopurification of complexes containing hOsa2 that was followed by mass spectrometry and immunoblotting demonstrated the presence of BRG1 and known BAFs, but not hOsa1 or hBRM. Deletion of the ARID did not compromise the integrity of the complex. Induction of hOsa2 expression caused impaired cell growth and accumulation of cells in the G0/G1 cell cycle phase. Elevated levels of the p53 and p21 proteins were detected in these cells while c-Myc mRNA and protein levels were found to decrease. Chromatin immunoprecipitation and reporter assays suggested that hOsa2 had a direct effect on c-myc and p21 promoter activity. Thus hOsa2 plays an important role in controlling genes regulating the cell cycle

The brain's energy economy excessively favors intrinsic, spontaneous neural activity over extrinsic, evoked activity, presumably to maintain its internal organization. Emerging hypotheses capable of explaining such an investment posit that the brain's intrinsic functional architecture encodes a blueprint for its repertoire of responses to the external world. Yet, there is little evidence directly linking intrinsic and extrinsic activity in the brain. Here we relate differences among individuals in the magnitude of task-evoked activity during performance of an Eriksen flanker task, to spontaneous oscillatory phenomena observed during rest. Specifically, we focused on the amplitude of low-frequency oscillations (LFO, 0.01-0.1Hz) present in the BOLD signal. LFO amplitude measures obtained during rest successfully predicted the magnitude of task-evoked activity in a variety of regions that were all activated during performance of the flanker task. In these regions, higher LFO amplitude at rest predicted higher task-evoked activity. LFO amplitude measures obtained during rest were also found to have robust predictive value for behavior. In midline cingulate regions, LFO amplitudes predicted not only the speed and consistency of performance but also the magnitude of the behavioral congruency effect embedded in the flanker task. These results support the emerging hypothesis that the brain's repertoire of responses to the external world are represented and updated in the brain's intrinsic functional architecture

Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behaviour, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain-stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these opponent social behaviours.

Amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, exacerbates Abeta-induced cell stress. The interaction of ABAD with Abeta exacerbates Abeta-induced mitochondrial and neuronal dysfunction. Here, we show that inhibition of the ABAD-Abeta interaction, using a decoy peptide (DP) in vitro and in vivo, protects against aberrant mitochondrial and neuronal function and improves spatial learning/memory. Intraperitoneal administration of ABAD-DP [fused to the transduction of human immunodeficiency virus 1-transactivator (Tat) protein and linked to the mitochondrial targeting sequence (Mito) (TAT-mito-DP) to transgenic APP mice (Tg mAPP)] blocked formation of ABAD-Abeta complex in mitochondria, increased oxygen consumption and enzyme activity associated with the mitochondrial respiratory chain, attenuated mitochondrial oxidative stress, and improved spatial memory. Similar protective effects were observed in Tg mAPP mice overexpressing neuronal ABAD decoy peptide (Tg mAPP/mito-ABAD). Notably, inhibition of the ABAD-Abeta interaction significantly reduced mitochondrial Abeta accumulation. In parallel, the activity of mitochondrial Abeta-degrading enzyme PreP (presequence peptidase) was enhanced in Tg mAPP mitochondria expressing the ABAD decoy peptide. These data indicate that segregating ABAD from Abeta protects mitochondria/neurons from Abeta toxicity; thus, ABAD-Abeta interaction is an important mechanism underlying Abeta-mediated mitochondrial and neuronal perturbation. Inhibitors of ABAD-Abeta interaction may hold promise as targets for the prevention and treatment of Alzheimer's disease.

Despite recent interest in reconstructing neuronal networks, complete wiring diagrams on the level of individual synapses remain scarce and the insights into function they can provide remain unclear. Even for Caenorhabditis elegans, whose neuronal network is relatively small and stereotypical from animal to animal, published wiring diagrams are neither accurate nor complete and self-consistent. Using materials from White et al. and new electron micrographs we assemble whole, self-consistent gap junction and chemical synapse networks of hermaphrodite C. elegans. We propose a method to visualize the wiring diagram, which reflects network signal flow. We calculate statistical and topological properties of the network, such as degree distributions, synaptic multiplicities, and small-world properties, that help in understanding network signal propagation. We identify neurons that may play central roles in information processing, and network motifs that could serve as functional modules of the network. We explore propagation of neuronal activity in response to sensory or artificial stimulation using linear systems theory and find several activity patterns that could serve as substrates of previously described behaviors. Finally, we analyze the interaction between the gap junction and the chemical synapse networks. Since several statistical properties of the C. elegans network, such as multiplicity and motif distributions are similar to those found in mammalian neocortex, they likely point to general principles of neuronal networks. The wiring diagram reported here can help in understanding the mechanistic basis of behavior by generating predictions about future experiments involving genetic perturbations, laser ablations, or monitoring propagation of neuronal activity in response to stimulation.