The excitability of individual dendritic branches is a plastic property of neurons. We found that experience in an enriched environment increased propagation of dendritic Na(+) spikes in a subset of individual dendritic branches in rat hippocampal CA1 pyramidal neurons and that this effect was mainly mediated by localized downregulation of A-type K(+) channel function. Thus, dendritic plasticity might be used to store recent experience in individual branches of the dendritic arbor.

Synaptic plasticity in adult neural circuits may involve the strengthening or weakening of existing synapses as well as structural plasticity, including synapse formation and elimination. Indeed, long-term in vivo imaging studies are beginning to reveal the structural dynamics of neocortical neurons in the normal and injured adult brain. Although the overall cell-specific morphology of axons and dendrites, as well as of a subpopulation of small synaptic structures, are remarkably stable, there is increasing evidence that experience-dependent plasticity of specific circuits in the somatosensory and visual cortex involves cell type-specific structural plasticity: some boutons and dendritic spines appear and disappear, accompanied by synapse formation and elimination, respectively. This Review focuses on recent evidence for such structural forms of synaptic plasticity in the mammalian cortex and outlines open questions.

We report the preparation and structure-activity relationships of phosphorus-containing histone deacetylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor growth inhibition in xenograft studies.

Cortical information processing is under state-dependent control of subcortical neuromodulatory systems. Although this modulatory effect is thought to be mediated mainly by slow nonsynaptic metabotropic receptors, other mechanisms, such as direct synaptic transmission, are possible. Yet, it is currently unknown if any such form of subcortical control exists. Here, we present direct evidence of a strong, spatiotemporally precise excitatory input from an ascending neuromodulatory center. Selective stimulation of serotonergic median raphe neurons produced a rapid activation of hippocampal interneurons. At the network level, this subcortical drive was manifested as a pattern of effective disynaptic GABAergic inhibition that spread throughout the circuit. This form of subcortical network regulation should be incorporated into current concepts of normal and pathological cortical function.

The adult central nervous system (CNS) of Drosophila is largely composed of relatively homogenous neuronal classes born during larval life. These adult-specific neuron lineages send out initial projections and then arrest development until metamorphosis, when intense sprouting occurs to establish the massive synaptic connections necessary for the behavior and function of the adult fly. In this study, we identified and characterized specific lineages in the adult CNS and described their secondary branch patterns. Because prior studies show that the outgrowth of incumbent remodeling neurons in the CNS is highly dependent on the ecdysone pathway, we investigated the role of ecdysone in the development of the adult-specific neuronal lineages using a dominant-negative construct of the ecdysone receptor (EcR-DN). When EcR-DN was expressed in clones of the adult-specific lineages, neuroblasts persisted longer, but we saw no alteration in the initial projections of the lineages. Defects were observed in secondary arbors of adult neurons, including clumping and cohesion of fine branches, misrouting, smaller arbors and some defasciculation. The defects varied across the multiple neuron lineages in both appearance and severity. These results indicate that the ecdysone receptor complex influences the fine-tuning of connectivity between neuronal circuits, in conjunction with other factors driving outgrowth and synaptic partnering.

We have approached the problem of reverse-engineering the flight control mechanism of the fruit fly by studying the dynamics of the responses to a visual stimulus during takeoff. Building upon a prior framework [G. Card and M. Dickinson, J. Exp. Biol., vol. 211, pp. 341-353, 2008], we seek to understand the strategies employed by the animal to stabilize attitude and orientation during these evasive, highly dynamical maneuvers. As a first step, we consider the dynamics from a gray-box perspective: examining lumped forces produced by the insect’s legs and wings. The reconstruction of the flight initiation dynamics, based on the unconstrained motion formulation for a rigid body, allows us to assess the fly’s responses to a variety of initial conditions induced by its jump. Such assessment permits refinement by using a visual tracking algorithm to extract the kinematic envelope of the wings [E. I. Fontaine, F. Zabala, M. Dickinson, and J. Burdick, "Wing and body motion during flight initiation in Drosophila revealed by automated visual tracking," submitted for publication] in order to estimate lift and drag forces [F. Zabala, M. Dickinson, and R. Murray, "Control and stability of insect flight during highly dynamical maneuvers," submitted for publication], and recording actual leg-joint kinematics and using them to estimate jump forces [F. Zabala, "A bio-inspired model for directionality control of flight initiation," to be published.]. In this paper, we present the details of our approach in a comprehensive manner, including the salient results.

Haloalkane dehalogenase (HD) catalyzes the hydrolysis of haloalkanes via a covalent enzyme-substrate intermediate. Fusing a target protein to an HD variant that cannot hydrolyze the intermediate enables labeling of the target protein with a haloalkane in cellulo. The utility of extant probes is hampered, however, by background fluorescence as well as limited membrane permeability. Here, we report on the synthesis and use of a fluorogenic affinity label that, after unmasking by an intracellular esterase, labels an HD variant in cellulo. Labeling is rapid and specific, as expected from the reliance upon enzymic catalysts and the high membrane permeance of the probe both before and after unmasking. Most notably, even high concentrations of the fluorogenic affinity label cause minimal background fluorescence without a need to wash the cells. We envision that such fluorogenic affinity labels, which enlist catalysis by two cellular enzymes, will find utility in pulse-chase experiments, high-content screening, and numerous other protocols.

In teleost fish, the Mauthner (M) cell, a large reticulospinal neuron in the brainstem, triggers escape behavior. Spinal commissural inhibitory interneurons that are electrotonically excited by the M-axon have been identified, but the behavioral roles of these neurons have not yet been addressed. Here, we studied these neurons, named CoLo (commissural local), in larval zebrafish using an enhancer-trap line in which the entire population of CoLos was visualized by green fluorescent protein. CoLos were present at one cell per hemi-segment. Electrophysiological recordings showed that an M-spike evoked a spike in CoLos via electrotonic transmission and that CoLos made monosynaptic inhibitory connections onto contralateral primary motoneurons, consistent with the results in adult goldfish. We further showed that CoLos were active only during escapes. We examined the behavioral roles of CoLos by investigating escape behaviors in CoLo-ablated larvae. The results showed that the escape behaviors evoked by sound/vibration stimuli were often impaired with a reduced initial bend of the body, indicating that CoLos play important roles in initiating escapes. We obtained several lines of evidence that strongly suggested that the impaired escapes occurred during bilateral activation of the M-cells: in normal larvae, CoLo-mediated inhibitory circuits enable animals to perform escapes even in these occasions by silencing the output of the slightly delayed firing of the second M-cell. This study illustrates (1) a clear example of the behavioral role of a specialized class of interneurons and (2) the capacity of the spinal circuits to filter descending commands and thereby produce the appropriate behavior.

Considerable progress has been made over the past couple of decades concerning the molecular bases of neurobehavioral function and dysfunction. The field of neurobehavioral genetics is becoming mature. Genetic factors contributing to neurologic diseases such as Alzheimer's disease have been found and evidence for genetic factors contributing to other diseases such as schizophrenia and autism are likely. This genetic approach can also benefit the field of behavioral neurotoxicology. It is clear that there is substantial heterogeneity of response with behavioral impairments resulting from neurotoxicants. Many factors contribute to differential sensitivity, but it is likely that genetic variability plays a prominent role. Important discoveries concerning genetics and behavioral neurotoxicity are being made on a broad front from work with invertebrate and piscine mutant models to classic mouse knockout models and human epidemiologic studies of polymorphisms. Discovering genetic factors of susceptibility to neurobehavioral toxicity not only helps identify those at special risk, it also advances our understanding of the mechanisms by which toxicants impair neurobehavioral function in the larger population. This symposium organized by Edward Levin and Annette Kirshner, brought together researchers from the laboratories of Michael Aschner, Douglas Ruden, Ulrike Heberlein, Edward Levin and Kathleen Welsh-Bohmer conducting studies with Caenorhabditis elegans, Drosophila, fish, rodents and humans studies to determine the role of genetic factors in susceptibility to behavioral impairment from neurotoxic exposure.