Matthew J. McGinley

Motor Cortex Feedback Influences Sensory Processing by Modulating Network State

Long-range corticocortical communication may have important roles in context-dependent sensory processing, yet we know very little about how these pathways influence their target regions. We studied the influence of primary motor cortex activity on primary somatosensory cortex in the mouse whisker system. We show that primary motor and somatosensory cortices undergo coherent, context-dependent changes in network state. Moreover, we show that motor cortex activity can drive changes in somatosensory cortex network state. A series of experiments demonstrate the involvement of the direct corticocortical feedback pathway, providing temporally precise and spatially targeted modulation of network dynamics. Cortically mediated changes in network state significantly impact sensory coding, with activated states increasing the reliability of responses to complex stimuli. By influencing network state, corticocortical communication from motor cortex may ensure that during active exploration the relevant sensory region is primed for enhanced sensory discrimination.

Triheteromeric NMDA Receptors at Hippocampal Synapses

NMDA receptors are composed of two GluN1 (N1) and two GluN2 (N2) subunits. Constituent N2 subunits control the pharmacological and kinetic characteristics of the receptor. NMDA receptors in hippocampal or cortical neurons are often thought of as diheteromeric, meaning that they contain only one type of N2 subunit. However, triheteromeric receptors with more than one type of N2 subunit also have been reported, and the relative contribution of diheteromeric and triheteromeric NMDA receptors at synapses has been difficult to assess. Because wild-type hippocampal principal neurons express N1, N2A, and N2B, we used cultured hippocampal principal neurons from N2A and N2B knock-out mice as templates for diheteromeric synaptic receptors. However, summation of N1/N2B and N1/N2A EPSCs could not account for the deactivation kinetics of wild-type EPSCs. To make a quantitative estimate of NMDA receptor subtypes at wild-type synapses, we used the deactivation kinetics and the effects of the competitive antagonist NVP-AAM077. Our results indicate that three types of NMDA receptors contribute to wild-type EPSCs, with at least two-thirds being triheteromeric receptors. Functional isolation of synaptic triheteromeric receptors revealed deactivation kinetics and pharmacology that were distinct from either diheteromeric receptor subtype. Because of differences in open probability, synaptic triheteromeric receptors outnumbered N1/N2A receptors by 5.8 to 1 and N1/N2B receptors by 3.2 to 1. Our results suggest that triheteromeric NMDA receptors must either be preferentially assembled or preferentially localized at synapses.

Distinct roles for two synaptotagmin isoforms in synchronous and asynchronous transmitter release at zebrafish neuromuscular junction

An obligatory role for the calcium sensor synaptotagmins in stimulus-coupled release of neurotransmitter is well established, but a role for synaptotagmin isoform involvement in asynchronous release remains conjecture. We show, at the zebrafish neuromuscular synapse, that two separate synaptotagmins underlie these processes. Specifically, knockdown of synaptotagmin 2 (syt2) reduces synchronous release, whereas knockdown of synaptotagmin 7 (syt7) reduces the asynchronous component of release. The zebrafish neuromuscular junction is unique in having a very small quantal content and a high release probability under conditions of either low-frequency stimulation or high-frequency augmentation. Through these features, we further determined that during the height of shared synchronous and asynchronous transmission these two modes compete for the same release sites.

Pupil fluctuations track rapid changes in adrenergic and cholinergic activity in cortex.

Rapid variations in cortical state during wakefulness have a strong influence on neural and behavioural responses and are tightly coupled to changes in pupil size across species. However, the physiological processes linking cortical state and pupil variations are largely unknown. Here we demonstrate that these rapid variations, during both quiet waking and locomotion, are highly correlated with fluctuations in the activity of corticopetal noradrenergic and cholinergic projections. Rapid dilations of the pupil are tightly associated with phasic activity in noradrenergic axons, whereas longer-lasting dilations of the pupil, such as during locomotion, are accompanied by sustained activity in cholinergic axons. Thus, the pupil can be used to sensitively track the activity in multiple neuromodulatory transmitter systems as they control the state of the waking brain.

Brain state dependent activity in the cortex and thalamus

Cortical and thalamocortical activity is highly state dependent, varying between patterns that are conducive to accurate sensory-motor processing, to states in which the brain is largely off-line and generating internal rhythms irrespective of the outside world. The generation of rhythmic activity occurs through the interaction of stereotyped patterns of connectivity together with intrinsic membrane and synaptic properties. One common theme in the generation of rhythms is the interaction of a positive feedback loop (e.g., recurrent excitation) with negative feedback control (e.g., inhibition, adaptation, or synaptic depression). The operation of these state-dependent activities has wide ranging effects from enhancing or blocking sensory-motor processing to the generation of pathological rhythms associated with psychiatric or neurological disorders.

Experience-dependent maturation of the glomerular microcircuit

Spontaneous and patterned activity, largely attributed to chemical transmission, shape the development of virtually all neural circuits. However, electrical transmission also has an important role in coordinated activity in the brain. In the olfactory bulb, gap junctions between apical dendrites of mitral cells increase excitability and synchronize firing within each glomerulus. We report here that the development of the glomerular microcircuit requires both sensory experience and connexin (Cx)36-mediated gap junctions. Coupling coefficients, which measure electrical coupling between mitral cell dendrites, were high in young mice, but decreased after postnatal day (P)10 because of a maturational increase in membrane conductance. Sensory deprivation, induced by unilateral naris occlusion at birth, slowed the morphological development of mitral cells and arrested the maturational changes in membrane conductance and coupling coefficients. As the coupling coefficients decreased in normal mice, a glutamate-mediated excitatory postsynaptic current (EPSC) between mitral cells emerged by P30. Although mitral–mitral EPSCs were generally unidirectional, they were not present in young adult Cx36−/− mice, suggesting that gap junctions are required for the development and/or function of the mature circuit. The experience-dependent transition from electrical transmission to combined chemical and electrical transmission provides a previously unappreciated mechanism that may tune the response properties of the glomerular microcircuit.

Generating synchrony from the asynchronous: compensation for cochlear traveling wave delays by the dendrites of individual brainstem neurons

Broadband transient sounds, such as clicks and consonants, activate a traveling wave in the cochlea. This wave evokes firing in auditory nerve fibers that are tuned to high frequencies several milliseconds earlier than in fibers tuned to low frequencies. Despite this substantial traveling wave delay, octopus cells in the brainstem receive broadband input and respond to clicks with submillisecond temporal precision. The dendrites of octopus cells lie perpendicular to the tonotopically organized array of auditory nerve fibers, placing the earliest arriving inputs most distally and the latest arriving closest to the soma. Here, we test the hypothesis that the topographic arrangement of synaptic inputs on dendrites of octopus cells allows octopus cells to compensate the traveling wave delay. We show that in mice the full cochlear traveling wave delay is 1.6 ms. Because the dendrites of each octopus cell spread across approximately one-third of the tonotopic axis, a click evokes a soma-directed sweep of synaptic input lasting 0.5 ms in individual octopus cells. Morphologically and biophysically realistic, computational models of octopus cells show that soma-directed sweeps with durations matching in vivo measurements result in the largest and sharpest somatic EPSPs. A low input resistance and activation of a low-voltage-activated potassium conductance that are characteristic of octopus cells are important determinants of sweep sensitivity. We conclude that octopus cells have dendritic morphologies and biophysics tailored to accomplish the precise encoding of broadband transient sounds.

Connections and synaptic function in the posteroventral cochlear nucleus of deaf jerker mice.

Mutations in the gene that encodes espins can cause deafness and vestibular disorders; mice that are homozygous for the autosomal recessive jerker mutation in the espin gene never hear. Extracellular injections of biocytin into the anteroventral cochlear nucleus (AVCN) revealed that although the cochlear nuclei are smaller in je/je mice, the topography in its innervation resembles that in wild‐type mice. Auditory nerve fibers innervate narrow, topographically organized, “isofrequency” bands in deaf animals over the ages examined, P18–P70. The projection of tuberculoventral cells was topographic in je/je as in wild‐type mice. Terminals of auditory nerve fibers in the multipolar cell area included both large and small endings, whereas in the octopus cell area they were exclusively small boutons in je/je as in wild‐type mice, but end bulbs near the nerve root of je/je animals were smaller than in hearing animals. In whole‐cell recordings from targets of auditory nerve fibers, octopus and T stellate cells, miniature excitatory postsynaptic currents (mEPSCs) had similar shapes as in +/+, indicating that the properties of AMPA receptors were not affected by the mutation. In je/je animals the frequency of spontaneous mEPSCs was elevated, and synaptic depression in responses to trains of shocks delivered at between 100 and 333 Hz was greater than in wild‐type mice, indicating that the probability of neurotransmitter release was increased. The frequency of spontaneous mEPSCs and extent of synaptic depression were greater in octopus than in T stellate cells, in both wild‐type and in je/je mice. J. Comp. Neurol. 510:297–308, 2008.

Knockout of Foxp2 disrupts vocal development in mice.

The FOXP2 gene is important for the development of proper speech motor control in humans. However, the role of the gene in general vocal behavior in other mammals, including mice, is unclear. Here, we track the vocal development of Foxp2 heterozygous knockout (Foxp2+/−) mice and their wildtype (WT) littermates from juvenile to adult ages, and observe severe abnormalities in the courtship song of Foxp2+/− mice. In comparison to their WT littermates, Foxp2+/− mice vocalized less, produced shorter syllable sequences, and possessed an abnormal syllable inventory. In addition, Foxp2+/− song also exhibited irregular rhythmic structure, and its development did not follow the consistent trajectories observed in WT vocalizations. These results demonstrate that the Foxp2 gene is critical for normal vocal behavior in juvenile and adult mice, and that Foxp2 mutant mice may provide a tractable model system for the study of the gene’s role in general vocal motor control.

Loss of olfactory cell adhesion molecule reduces the synchrony of mitral cell activity in olfactory glomeruli

Non‐technical summary  In olfactory bulb glomeruli, incoming sensory input from the nose (axodendritic synapses) is segregated from local intraglomerular interactions (dendrodendritic synapses). We examined the synchrony of neural activity within glomeruli using knockout mice in which loss of olfactory cell adhesion molecule disrupts clustering of synaptic compartments. Using paired whole‐cell recording of mitral cells within a single glomerulus in brain slices, synchrony of fast and slow neural activity was reduced. However, incoming afferent activity and dendrodendritic inhibition were unaffected. We suggest that compartmentalization of synapses in the glomerulus is important for processing of olfactory sensory information.