Summary R/qtl is an extensible, interactive environment for mapping quantitative trait loci (QTLs) in experimental populations derived from inbred lines. It is implemented as an add-on package for the freely-available statistical software, R, and includes functions for estimating genetic maps, identifying genotyping errors, and performing single-QTL and two-dimensional, two-QTL genome scans by multiple methods, with the possible inclusion of covariates. Availability The package is freely available at http://www.biostat.jhsph.edu/~kbroman/qtl.

R/qtl: QTL mapping in experimental crosses

Activity has an important role in refining synaptic connectivity during development, in part through 'Hebbian' mechanisms such as long-term potentiation and long-term depression. However, Hebbian plasticity is probably insufficient to explain activity-dependent development because it tends to destabilize the activity of neural circuits. How can complex circuits maintain stable activity states in the face of such destabilizing forces? An idea that is emerging from recent work is that average neuronal activity levels are maintained by a set of homeostatic plasticity mechanisms that dynamically adjust synaptic strengths in the correct direction to promote stability. Here we discuss evidence from a number of systems that homeostatic synaptic plasticity is crucial for processes ranging from memory storage to activity-dependent development.

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Homeostatic plasticity in the developing nervous system

Neuronal circuits in the brain are shaped by experience during 'critical periods' in early postnatal life. In the primary visual cortex, this activity-dependent development is triggered by the functional maturation of local inhibitory connections and driven by a specific, late-developing subset of interneurons. Ultimately, the structural consolidation of competing sensory inputs is mediated by a proteolytic reorganization of the extracellular matrix that occurs only during the critical period. The reactivation of this process, and subsequent recovery of function in conditions such as amblyopia, can now be studied with realistic circuit models that might generalize across systems.

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Critical period plasticity in local cortical circuits.

Sleep function and synaptic homeostasis.

Recognizing the enormous potential of DNA markers in plant breeding, many agricultural research centers and plant breeding institutes have adopted the capacity for marker development and marker-assisted selection (MAS). However, due to rapid developments in marker technology, statistical methodology for identifying quantitative trait loci (QTLs) and the jargon used by molecular biologists, the utility of DNA markers in plant breeding may not be clearly understood by non-molecular biologists. This review provides an introduction to DNA markers and the concept of polymorphism, linkage analysis and map construction, the principles of QTL analysis and how markers may be applied in breeding programs using MAS. This review has been specifically written for readers who have only a basic knowledge of molecular biology and/or plant genetics. Its format is therefore ideal for conventional plant breeders, physiologists, pathologists, other plant scientists and students.

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An introduction to markers, quantitative trait loci (QTL) mapping and marker-assisted selection for crop improvement: The basic concepts

Map Manager QTX (QTX) is software for analysis of genetic mapping experiments in experimental plants and animals. It includes functions for mapping both Mendelian and quantitative trait loci. QTX is an enhanced version of Map Manager QT, rewritten with the aid of cross-platform libraries (XVT, Boulder Software Foundry, Inc.), which allow it to be compiled for multiple computer platforms. It currently is distributed for Microsoft Windows and Mac OS and is available at http://mapmgr.roswellpark.org/mmQTX.html.

Map Manager QTX, cross-platform software for genetic mapping.

The mechanisms underlying experience-dependent plasticity and refinement of central circuits are not yet fully understood. A non-Hebbian form of synaptic plasticity, which scales synaptic strengths up or down to stabilize firing rates, has recently been discovered in cultured neuronal networks. Here we demonstrate the existence of a similar mechanism in the intact rodent visual cortex. The frequency of miniature excitatory postsynaptic currents (mEPSCs) in principal neurons increased steeply between post-natal days 12 and 23. There was a concomitant decrease in mEPSC amplitude, which was prevented by rearing rats in complete darkness from 12 days of age. In addition, as little as two days of monocular deprivation scaled up mEPSC amplitude in a layer- and age-dependent manner. These data indicate that mEPSC amplitudes can be globally scaled up or down as a function of development and sensory experience, and suggest that synaptic scaling may be involved in the activity-dependent refinement of cortical connectivity.

Critical periods for experience-dependent synaptic scaling in visual cortex.

Neuronal excitability has a large impact on network behavior, and plasticity in intrinsic excitability could serve as an important information storage mechanism. Here we ask whether postsynaptic excitability of layer V pyramidal neurons from primary visual cortex can be rapidly regulated by activity. Whole cell current-clamp recordings were obtained from visual cortical slices, and intrinsic excitability was measured by recording the firing response to small depolarizing test pulses. Inducing neurons to fire at high-frequency (30-40 Hz) in bursts for 5 min in the presence of synaptic blockers increased the firing rate evoked by the test pulse. This long-term potentiation of intrinsic excitability (LTP-IE) lasted for as long as we held the recording (>60 min). LTP-IE was accompanied by a leftward shift in the entire frequency versus current (F-I) curve and a decrease in threshold current and voltage. Passive neuronal properties were unaffected by the induction protocol, indicating that LTP-IE occurred through modification in voltage-gated conductances. Reducing extracellular calcium during the induction protocol, or buffering intracellular calcium with bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid, prevented LTP-IE. Finally, blocking protein kinase A (PKA) activation prevented, whereas pharmacological activation of PKA both mimicked and occluded, LTP-IE. This suggests that LTP-IE occurs through postsynaptic calcium influx and subsequent activation of PKA. Activity-dependent plasticity in intrinsic excitability could greatly expand the computational power of individual neurons.

Long-term potentiation of intrinsic excitability in LV visual cortical neurons.

Regulation of AMPA receptor (AMPAR) membrane trafficking is critical for synaptic plasticity, as well as for learning and memory. However, the mechanisms of AMPAR trafficking in vivo remain elusive. Using in vivo two-photon microscopy in the mouse somatosensory barrel cortex, we found that acute whisker stimulation led to a significant increase in the intensity of surface AMPAR GluA1 subunit (sGluA1) in both spines and dendritic shafts and a small increase in spine size relative to prestimulation values. Interestingly, the initial spine properties biased spine changes following whisker stimulation. Changes in spine sGluA1 intensity were positively correlated with changes in spine size and dendritic shaft sGluA1 intensity following whisker stimulation. The increase in spine sGluA1 intensity evoked by whisker stimulation was NMDA receptor dependent and long lasting, similar to major forms of synaptic plasticity in the brain. In this study we were able to observe experience-dependent AMPAR trafficking in real time and characterize, in vivo, a major form of synaptic plasticity in the brain.

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Visualization of NMDA receptor - Dependent AMPA receptor synaptic plasticity in vivo

Homeostatic plasticity of neuronal intrinsic excitability (HPIE) operates to maintain networks within physiological bounds in response to chronic changes in activity. Classically, this form of plasticity adjusts the output firing level of the neuron through the regulation of voltage-gated ion channels. Ion channels also determine spike timing in individual neurons by shaping subthreshold synaptic and intrinsic potentials. Thus, an intriguing hypothesis is that HPIE can also regulate network synchronization. We show here that the dendrotoxin-sensitive D-type K+ current (ID) disrupts the precision of AP generation in CA3 pyramidal neurons and may, in turn, limit network synchronization. The reduced precision is mediated by the sequence of outward ID followed by inward Na+ current. The homeostatic downregulation of ID increases both spike-time precision and the propensity for synchronization in iteratively constructed networks in vitro. Thus, network synchronization is adjusted in area CA3 through activity-dependent remodeling of ID.

https://www.jneurosci.org/content/jneuro/30/38/12885.full.pdf

Robert H. Cudmore

Papers

Map Manager QTX, cross-platform software for genetic mapping.

Critical periods for experience-dependent synaptic scaling in visual cortex.

Long-term potentiation of intrinsic excitability in LV visual cortical neurons.

Visualization of NMDA receptor - Dependent AMPA receptor synaptic plasticity in vivo

Spike-Time Precision and Network Synchrony Are Controlled by the Homeostatic Regulation of the D-Type Potassium Current