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Lyngholm, D.

Publications and source records attributed to Lyngholm, D..

3 recordsLinked to original sources

Non-canonical role for Lpar1-EGFP subplate neurons in early postnatal somatosensory cortex

Subplate neurons (SPNs) are a transient neuronal population shown to play a key role in nascent sensory processing relaying thalamic information to the developing cerebral cortex. However there is little understanding of how heterogeneity within this population relates to emergent function. To address this question we employed optical and electrophysiological technologies to investigate the synaptic connectivity of SPNs defined by expression of the Lpar1-EGFP transgene through the first postnatal week in primary whisker somatosensory cortex (S1BF) in mouse. Our data identify that the Lpar1-EGFP SPNs represent two morphological subtypes: (1) transient, fusiform SPNs with axons largely restricted to the subplate zone; (2) pyramidal SPNs with axon collaterals that traverse the overlying cortex to extend through the marginal zone. Laser scanning photostimulation of caged glutamate was used to determine columnar glutamatergic and GABAergic input onto both of these SPN subtypes. These experiments revealed that the former receive translaminar input from more superficial cortical layers up until the emergence of the whisker barrels (~postnatal (P)5). In contrast, pyramidal SPNs only receive local input from the adjacent subplate network at early ages but then at later ages can acquire varied input from the overlying cortex. Combined electrical stimulation of the ventral posterior nucleus of the thalamus and optogenetic activation of thalamic afferents in thalamocortical slice preparations revealed that Lpar1-EGFP SPNs only receive sparse thalamic innervation during early postnatal development. Taken together, these data reveal two components of the postnatal network that interpret sparse thalamic input to direct the emergent columnar structure of neonatal somatosensory cortex.

neuroscience↗

Measuring and Modelling the Emergence of Order in the Mouse Retinocollicular Projection

In the formation of retinotopic maps both experimental and theoretical work implicate guidance molecules and patterned neuronal activity. A common view is that molecular cues define and activity cues refine mappings. Important insights have come from studies of the retinocollicular projection in transgenic mice, in which cues have been modified either in isolation or in combination. Mostly these have generated descriptions of endpoint mappings. The dynamics of map formation remain under-explored experimentally and computationally. We have quantified changes in the ordering of the mouse retinocollicular projection with age after making local collicular injections of fluorescent microspheres. Contour analysis shows that, at birth (P0), cells from over 80% of the retina converge on a given collicular locus; this percentage falls gradually to P4 then rapidly approaches adult values by P12. Paired injections reveal how the segregation of labelled cells depends both on injection site separation and relative orientation and also age. At P0, large anterior-posterior separations failed to produce segregated label: segregation improved with a similar timecourse to convergence to reach near adult-values by P12. An implementation of a combined activity-molecular model captures these segregation dynamics.\n\nThe developmental dynamics were then studied in the nAChR-{beta}2-/- mouse, which has altered patterns of retinal activity in the first postnatal week that results in a more diffuse adult retinal projection. Surprisingly, both measures of map refinement (convergence and segregation) remain largely constant and imprecise in the first postnatal week - only subsequently does the projection begin to refine. Substituting nAChR-{beta}2-/- activity patterns for wild-type patterns [5] into the model failed to capture the biology: refinement was initially faster. By reducing the relative importance of the gradients contribution to the model energy (to 15% of normal) we were able to mimic the delayed refinement observed in vivo. Our model therefore predicts the altered activity patterns may affect readout of guidance cues.

neuroscience↗

Cre-dependent optogenetic transgenic mice without early age-related hearing loss

With the advent of recent genetic technologies for mice, it is now feasible to investigate the circuit mechanisms of brain functions in an unprecedented manner. Although transgenic mice are commonly used on C57BL/6J (C57) background, hearing research has typically relied on different genetic backgrounds, such as CBA/Ca or CBA due to the genetic defect of C57 mice for early age-related hearing loss. This limits the utilization of available genetic resources for hearing research. Here we report congenic (>F10) Cre-dependent channelrhodopsin2 (ChR2) mice on CBA/Ca background. By crossing this line with Cre-driver mice on C57 background, F1 hybrids restored the hearing deficit of C57 mice. We also found a linear relationship between aging and hearing loss, with progression rates varied depending on genetic backgrounds (3.39 dB/month for C57; 0.82 dB/month for F1 hybrid). We further demonstrate that this approach allows to express ChR2 in a specific type of inhibitory neurons in the auditory cortex and that they can be identified within a simultaneously recorded population of neurons in awake mice. Thus, our Cre-dependent optogenetic transgenic mice on CBA/Ca background are a valuable tool to investigate the circuit mechanisms of hearing across lifespan.

neuroscience↗