Biomedical subjects

Asaf Keller

Publications and source records attributed to Asaf Keller.

15 recordsLinked to original sources

PubMed2006

Cortical control of a whisking central pattern generator.

Whether the motor cortex regulates voluntary movements by generating the motor pattern directly or by acting through subcortical central pattern generators (CPGs) remains a central question in motor control. Using the rat whisker system, an important model system of mammalian motor control, we develop an anesthetized preparation to investigate the interaction between the motor cortex and a whisking CPG. Using this model we investigate the involvement of a serotonergic component of the whisking CPG in determining whisking kinematics and the mechanisms through which drive from the CPG is converted into movements by vibrissa motor units. Consistent with an action of the vibrissa motor cortex (vMCx) on a subcortical CPG, the frequency of whisking evoked by intracortical microstimulation (ICMS) of vMCx differed significantly from the stimulation frequency, whereas whisking onset latencies correlated negatively with stimulation intensity. Further, ICMS-evoked whisking was suppressed by a serotonin receptor antagonist, supporting previous findings that the whisking CPG contains a significant serotonergic component. The amplitude of ICMS-evoked whisking was correlated with the number of active motor units-isolated from vibrissal EMGs or recorded directly from vibrissa motoneurons-and their activity level. In addition, whisking frequency was correlated with the firing rate of these motoneurons. These findings support the hypothesis that vMCx regulates whisking through its actions on a subcortical CPG.

Animals↗

PubMed2005

Anticipatory activity of motor cortex in relation to rhythmic whisking.

Rats characteristically generate stereotyped exploratory (5-12 Hz) whisker movements, which can also be adaptively modulated. Here we tested the hypothesis that the vibrissal representation in motor cortex (vMCx) initiates and modulates whisking by acting on a subcortical whisking central pattern generator (CPG). We recorded local field potentials (LFPs) in vMCx of behaving Sprague-Dawley rats while monitoring whisking behavior through mystacial electromyograms (EMGs). Recordings were made during free exploration, under body restraint, or in a head-fixed animal. LFP activity increased significantly prior to the onset of a whisking epoch and ended prior to the epoch's termination. In addition, shifts in whisking kinematics within a whisk epoch were often reflected in changes in LFP activity. These data support the hypothesis that vMCx may initiate and modulate whisking behavior through its action on a subcortical CPG.

Action Potentials↗

PubMed2005

The role of thalamic inputs in surround receptive fields of barrel neurons.

Controversy exists regarding the relative roles of thalamic versus intracortical inputs in shaping the response properties of cortical neurons. In the whisker-barrel system, this controversy centers on the mechanisms determining the receptive fields of layer IV (barrel) neurons. Whereas principal whisker-evoked responses are determined by thalamic inputs, the mechanisms responsible for adjacent whisker (AW) responses are in dispute. Here, we took advantage of the fact that lesions of the spinal trigeminal nucleus interpolaris (SpVi) significantly reduce the receptive field size of neurons in the ventroposterior thalamus. We reasoned that if AW responses are established by these thalamic inputs, brainstem lesions would significantly reduce the receptive field sizes of barrel neurons. We obtained extracellular single unit recordings from barrel neurons in response to whisker deflections from control rats and from rats that sustained SpVi lesions. After SpVi lesions, the receptive field of both excitatory and inhibitory barrel neurons decreased significantly in size, whereas offset/onset response ratios increased. Response magnitude decreased only for inhibitory neurons. All of these findings are consistent with the hypothesis that AW responses are determined primarily by direct thalamic inputs and not by intracortical interactions.

Animals↗

PubMed2004

Reducing the uncertainty: gating of peripheral inputs by zona incerta.

Sensory inputs are relayed to the neocortex by "first-order" thalamic nuclei, the responses of which are determined by ascending inputs from peripheral receptors. In contrast, "higher-order" thalamic nuclei respond poorly to peripheral inputs, and their responses are thought to be determined by descending cortical inputs. We tested this hypothesis by recording from neurons in the higher-order somatosensory posterior medial (POm) nucleus of narcotized rats. As reported previously, POm neurons responded to whisker stimuli with long-latency (median, 27 msec) and low-magnitude responses, consistent with cortically driven responses. However, when we suppressed inhibitory inputs from the subthalamic nucleus zona incerta (ZI), POm responses were of significantly higher magnitude and shorter latency, with many POm neurons responding at latencies consistent with ascending driving inputs from trigeminal nuclei. Our data suggest that POm comprises two neuronal populations: one population is driven by both peripheral and cortical inputs, and the second population responds only to cortical inputs. These findings demonstrate that ZI gates peripheral inputs to POm, enabling it to function both as a first-order and higher-order nucleus. Because ZI innervates all higher-order nuclei, this gating mechanism may exert similar regulation of thalamic processing in other sensory systems.

Afferent Pathways↗

PubMed2004

Robust temporal coding in the trigeminal system.

The ability of rats to use their whiskers for fine tactile discrimination rivals that of humans using their fingertips. Rats perform discriminations rapidly and accurately while palpating the environment with their whiskers. This suggests that whisker deflections produce a robust and reliable neural code. Whisker primary afferents respond with highly reproducible temporal spike patterns to transient stimuli. Here we show that, with the use of a linear kernel, any of these reproducible response trains recorded from an individual neuron can reliably predict complex whisker deflections. These predictions are significantly improved by integrating responses from neurons with opposite angular preferences.

Acoustic Stimulation↗

PubMed2004

Response properties of whisker-related neurons in rat second somatosensory cortex.

In addition to a primary somatosensory cortex (SI), the cerebral cortex of all mammals contains a second somatosensory area (SII); however, the functions of SII are largely unknown. Our aim was to explore the functions of SII by comparing response properties of whisker-related neurons in this area with their counterparts in the SI. We obtained extracellular unit recordings from narcotized rats, in response to whisker deflections evoked by a piezoelectric device, and compared response properties of SI barrel (layer IV) neurons with those of SII (layers II to VI) neurons. Neurons in both cortical areas have similar response latencies and spontaneous activity levels. However, SI and SII neurons differ in several significant properties. The receptive fields of SII neurons are at least five times as large as those of barrel neurons, and they respond equally strongly to several principal whiskers. The response magnitude of SII neurons is significantly smaller than that of neurons in SI, and SII neurons are more selective for the angle of whisker deflection. Furthermore, whereas in SI fast-spiking (inhibitory) and regular-spiking (excitatory) units have different spontaneous and evoked activity levels and differ in their responses to stimulus onset and offset, SII neurons do not show significant differences in these properties. The response properties of SII neurons suggest that they are driven by thalamic inputs that are part of the paralemniscal system. Thus whisker-related inputs are processed in parallel by a lemniscal system involving SI and a paralemniscal system that processes complimentary aspects of somatosensation.

Animals↗

PubMed2004

Precise temporal responses in whisker trigeminal neurons.

The ability of rats using their whiskers to perform fine tactile discrimination rivals that of humans using their fingertips. Rats must perform these discriminations rapidly and accurately while palpating the environment with their whiskers. This suggests that whisker-derived inputs produce a robust and reliable code, capable of capturing complex, high-frequency information. The first neural representation of whisker-derived stimulus information is in primary afferent neurons of the trigeminal ganglion. Here we demonstrate that there is a continuum of direction-dependent response profiles in trigeminal neurons and provide the first quantitative analysis of the encoding of complex stimuli by these neurons. We show that all classes of trigeminal ganglion neurons respond with highly reproducible temporal spike patterns to transient stimuli. Such a robust coding mechanism may allow rapid perception of complex tactile features.

Action Potentials↗

PubMed2003

Intercellular interactions in the mammalian olfactory nerve.

The small, unmyelinated axons of olfactory sensory neurons project to the olfactory bulb in densely packed fascicles, an arrangement conducive to axo-axonal interactions. We recently demonstrated ephaptic interactions between these axons in the olfactory nerve layer, the layer of the olfactory bulb in which the axon fascicles interweave and rearrange extensively. In the present study, we hypothesized that the axons, which express connexins, may have another mode of communication: gap junctions. Previous transmission electron microscopy (TEM) studies have failed to demonstrate such junctions. However, the definitive method for detecting gap junctions, freeze fracture, has not been used to examine the interaxonal connections of the olfactory nerve layer. Here, we apply a combined approach of TEM and freeze fracture to determine if gap junctions are present between the olfactory axons. Gap junctions involving olfactory axons were not found. However, by freeze fracture, P faces of both the axons and ensheathing cells (glia that surround the axon fascicles) contained distinctive linear arrays of particles, aligned along the small columns of extracellular space. In axons, few intramembranous particles were present outside of these arrays. Multi-helix proteins, including ion channels and connexin hemichannels, have been shown to be visible as particles by freeze fracture. This suggests that the proteins important for signal transmission are confined to the linear arrays. Such an arrangement would facilitate ephaptic transmission, calcium waves, current oscillations, and paracrine communication and may be important for olfactory neural code processing.

Animals↗

PubMed2003

GCP II (NAALADase) inhibition suppresses mossy fiber-CA3 synaptic neurotransmission by a presynaptic mechanism.

We tested the hypothesis that endogenous N-acetylaspartylglutamate (NAAG) presynaptically inhibits glutamate release at mossy fiber-CA3 synapses. For this purpose, we made use of 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), an inhibitor of glutamate carboxypeptidase II [GCP II; also known as N-acetylated alpha-linked acidic dipeptidase (NAALADase)], the enzyme that hydrolyzes NAAG into N-acetylaspartate and glutamate. Application of 2-MPPA (1-20 microM) had no effect on intrinsic membrane properties of CA3 pyramidal neurons recorded in vitro in whole cell current- or voltage-clamp mode. Bath application of 10 microM 2-MPPA suppressed evoked excitatory postsynaptic current (EPSC) amplitudes. Attenuation of EPSC amplitudes was accompanied by a significant increase in paired-pulse facilitation (50-ms interpulse intervals), suggesting that a presynaptic mechanism is involved. The group II metabotropic glutamate receptor (mGluR) antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-y l) propanoic acid (LY341495) prevented the 2-MPPA-dependent suppression of EPSC amplitudes. 2-MPPA reduced the frequencies of TTX-insensitive miniature EPSCs (mEPSC), without affecting their amplitudes, further supporting a presynaptic action for GCP II inhibition. 2-MPPA-induced reduction of mEPSC frequencies was prevented by LY341495, reinforcing the role of presynaptic group II mGluR. Because GCP II inhibition is thought to increase NAAG levels, these results suggest that NAAG suppresses synaptic transmission at mossy fiber-CA3 synapses through presynaptic activation of group II mGluRs.

Amino Acids↗

PubMed2003

Serotonin regulates rhythmic whisking.

Many rodents explore their environment by rhythmically palpating objects with their mystacial whiskers. These rhythmic whisker movements ("whisking"; 5-9 Hz) are thought to be regulated by an unknown brainstem central pattern generator (CPG). We tested the hypothesis that serotonin (5-HT) inputs to whisking facial motoneurons (wFMNs) are part of this CPG. In response to exogenous serotonin, wFMNs recorded in vitro fire rhythmically at whisking frequencies, and selective 5-HT2 or 5-HT3 receptor antagonists suppress this rhythmic firing. In vivo, stimulation of brainstem serotonergic raphe nuclei evokes whisker movements. Unilateral infusion of selective 5-HT2 or 5-HT3 receptor antagonists suppresses ipsilateral whisking and substantially alters the frequencies and symmetry of whisker movements. These findings suggest that serotonin is both necessary and sufficient to generate rhythmic whisker movements and that serotonergic premotoneurons are part of a whisking CPG.

Animals↗

PubMed2003

Whisker motor cortex ablation and whisker movement patterns.

Previous studies, based on qualitative observations, reported that lesions of the whisker motor cortex produce no deficits in whisking behavior. We used high-resolution optoelectronic recording methods to compare the temporal organization and kinematics of whisker movements before and after unilateral lesions of whisker motor cortex in rats. We now report that while the lesion did not abolish whisking, it significantly disrupted whisking kinematics, coordination, and temporal organization. Lesioned animals showed significant increases in the velocity and amplitude of whisker protractions contralateral to the lesions, as well as a reduction in the synchrony of whisker movements on the two sides of the face. There was a marked shift in the distribution of whisking frequencies, with reduction of activity in the 5-7 Hz bandwidth and increased activity at < 2 Hz. Disruptions of the normal whisking pattern were evident on both sides of the face, and the magnitude of these effects was proportional to the extent of the cortical ablation. We suggest that the observed deficits reflect an imbalance in cortical inputs to a brainstem central pattern generator.

Animals↗

PubMed2003

The glial sling is a migratory population of developing neurons.

For two decades the glial sling has been hypothesized to act as a guidance substratum for developing callosal axons. However, neither the cellular nature of the sling nor its guidance properties have ever been clearly identified. Although originally thought to be glioblasts, we show here that the subventricular zone cells forming the sling are in fact neurons. Sling cells label with a number of neuronal markers and display electrophysiological properties characteristic of neurons and not glia. Furthermore, sling cells are continuously generated until early postnatal stages and do not appear to undergo widespread cell death. These data indicate that the sling may be a source of, or migratory pathway for, developing neurons in the rostral forebrain, suggesting additional functions for the sling independent of callosal axon guidance.

Animals↗

PubMed2002

Functional circuitry involved in the regulation of whisker movements.

Neuroanatomical tract-tracing methods were used to identify the oligosynaptic circuitry by which the whisker representation of the motor cortex (wMCx) influences the facial motoneurons that control whisking activity (wFMNs). Injections of the retrograde tracer cholera toxin subunit B into physiologically identified wFMNs in the lateral facial nucleus resulted in dense, bilateral labeling throughout the brainstem reticular formation and in the ambiguus nucleus as well as predominantly ipsilateral labeling in the paralemniscal, pedunculopontine tegmental, Kölliker-Fuse, and parabrachial nuclei. In addition, neurons in the following midbrain regions projected to the wFMNs: superior colliculus, red nucleus, periaqueductal gray, mesencephalon, pons, and several nuclei involved in oculomotor behaviors. Injections of the anterograde tracer biotinylated dextran amine into the wMCx revealed direct projections to the brainstem reticular formation as well as multiple brainstem and midbrain structures shown to project to the wFMNs. Regions in which retrograde labeling and anterograde labeling overlap most extensively include the brainstem parvocellular, gigantocellular, intermediate, and medullary (dorsal and ventral) reticular formations; ambiguus nucleus; and midbrain superior colliculus and deep mesencephalic nucleus. Other regions that contain less dense regions of combined anterograde and retrograde labeling include the following nuclei: the interstitial nucleus of medial longitudinal fasciculus, the pontine reticular formation, and the lateral periaqueductal gray. Premotoneurons that receive dense inputs from the wMCx are likely to be important mediators of cortical regulation of whisker movements and may be a key component in a central pattern generator involved in the generation of rhythmic whisking activity.

Animals↗

PubMed2002

Use-dependent inhibition of dendritic spines.

Dendritic spines are now known to be subject to use-dependent plasticity that affects both their structure and their numbers. Recently, it has been demonstrated that a use-dependent increase in the density of dendritic spines occurs in both excitatory and inhibitory synapses in the mouse barrel cortex. Furthermore, it has been shown that although this increase in the density of spines and excitatory synapses is transient, the increase in spinous inhibitory synapses is long-lasting. These findings lend further support to the hypothesis that synapses in the mature cortex are subject to continual use-dependent plasticity.

Animals↗

PubMed2002

Functional independence of layer IV barrels.

Our aim was to investigate the patterns of functional inputs and outputs from individual barrels in the mouse somatosensory cortex, and to test the hypothesis that individual barrels in layer IV are functionally independent of direct inputs from neighboring barrels. In a mouse in vitro slice preparation of the barrel cortex, we recorded voltage-sensitive dye signals evoked in response to microstimulation of a single barrel. Activity propagated from the stimulated barrel to the supragranular layers, where it spread to activate several barrel columns. However, in no instance did activity propagate directly from the stimulated barrel to neighboring barrels. Neither suppression of GABAergic inhibition, nor activation of N-methyl-D-aspartate receptors, revealed direct interbarrel interactions. By contrast, microstimulation in the supra- or infragranular layers resulted in direct propagation of activity to neighboring barrel columns. We conclude that the neurons within individual barrels are functionally independent of direct inputs from neighboring barrels. This suggests that the response properties of layer IV barrel neurons are shaped primarily by their presynaptic thalamic afferents and by intrabarrel interactions, and that these responses are independent of direct inputs from neighboring barrels.

2-Amino-5-phosphonovalerate↗