Dieter Jaeger

Membrane Potential Synchrony of Simultaneously Recorded Striatal Spiny Neurons In Vivo

The basal ganglia are an interconnected set of subcortical regions whose established role in cognition and motor control remains poorly understood. An important nucleus within the basal ganglia, the striatum, receives cortical afferents that convey sensorimotor, limbic and cognitive information. The activity of medium-sized spiny neurons in the striatum seems to depend on convergent input within these information channels. To determine the degree of correlated input, both below and at threshold for the generation of action potentials, we recorded intracellularly from pairs of spiny neurons in vivo. Here we report that the transitions between depolarized and hyperpolarized states were highly correlated among neurons. Within individual depolarized states, some significant synchronous fluctuations in membrane potential occurred, but action potentials were not synchronized. Therefore, although the mean afferent signal across fibres is highly correlated among striatal neurons, the moment-to-moment variations around the mean, which determine the timing of action potentials, are not. We propose that the precisely timed, synchronous component of the membrane potential signals activation of cell assemblies and enables firing to occur. The asynchronous component, with low redundancy, determines the fine temporal pattern of spikes.

Prolonged responses in rat cerebellar Purkinje cells following activation of the granule cell layer: an intracellular in vitro and in vivo investigation.

We obtained intracellular recordings of 84 Purkinje cells in vitro from guinea pig slices and of 35 cells in vivo from ketamine-anesthetized rats in order to assess detailed properties of synaptic responses in Purkinje cells following granule cell activation. In vitro, electrical stimulation of the granule cell layer underlying recorded Purkinje cells was used in sagittal slices to predominantly activate synapses on ascending granule cell axons. In vivo, stimulation of the upper lip was used to activate Purkinje cells overlying the upper lip patch in the granule cell layer of crus IIa. In the presence of a GABAA antagonist, Purkinje cells at resting membrane potential responded to both electrical stimulation in vitro and peripheral stimulation in vivo, with a depolarization of 1–10 mV amplitude that lasted for 100–300 ms in the absence of climbing fiber input. Similar prolonged depolarizations could also be induced by brief depolarizing current pulses delivered through the recording electrode, demonstrating that either synaptic or direct depolarization may activate inward currents leading to a sustained response. In support of this hypothesis we found that prolonged depolarizations were shortened significantly when stimulation in the granule cell layer or intracellular current pulses were delivered during hyperpolarizing current steps. Stimulation in the granule cell layer or intracellular current pulses delivered during periods of spontaneous somatic spiking resulted in prolonged depolarizations in dendritic recordings, which were accompanied by an increase in somatic spiking frequency. Following upper lip stimulation in vivo, this increase in somatic spiking was interrupted by an inhibition of 10–50 ms duration. In a majority of recordings, this inhibition did not completely abolish prolonged depolarizations, however, and a delayed increase in somatic spike frequency was still observed. These results suggest that prolonged increases in Purkinje cell spike frequency following peripheral stimulation are due to an underlying prolonged dendritic depolarization induced by granule cell input. Further, a single, short burst of input via ascending granule cell axons appears to be sufficient to induce these responses.

Infraslow LFP correlates to resting-state fMRI BOLD signals

The slow fluctuations of the blood-oxygenation-level dependent (BOLD) signal in resting-state fMRI are widely utilized as a surrogate marker of ongoing neural activity. Spontaneous neural activity includes a broad range of frequencies, from infraslow (<0.5 Hz) fluctuations to fast action potentials. Recent studies have demonstrated a correlative relationship between the BOLD fluctuations and power modulations of the local field potential (LFP), particularly in the gamma band. However, the relationship between the BOLD signal and the infraslow components of the LFP, which are directly comparable in frequency to the BOLD fluctuations, has not been directly investigated. Here we report a first examination of the temporal relation between the resting-state BOLD signal and infraslow LFPs using simultaneous fMRI and full-band LFP recording in rat. The spontaneous BOLD signal at the recording sites exhibited significant localized correlation with the infraslow LFP signals as well as with the slow power modulations of higher-frequency LFPs (1-100 Hz) at a delay comparable to the hemodynamic response time under anesthesia. Infraslow electrical activity has been postulated to play a role in attentional processes, and the findings reported here suggest that infraslow LFP coordination may share a mechanism with the large-scale BOLD-based networks previously implicated in task performance, providing new insight into the mechanisms contributing to the resting state fMRI signal.

Neuronal activity in the striatum and pallidum of primates related to the execution of externally cued reaching movements

We studied changes in basal ganglia neuronal activity associated with reaching movements of the arm in two monkeys. Data were obtained from 427 single neuronal units in putamen, 199 in caudate nucleus, and 216 in globus pallidus with multiwire electrodes allowing simultaneous recordings from multiple neurons. In all structures, changes in activity related to movement occurred most often after the onset of EMG: 43% of tested neurons in the putamen, 32% in the caudate nucleus, and 38% in the globus pallidus. Less frequently, changes began before EMG activation: 20% of neurons in the putamen, 19% in caudate nucleus, and 17% in globus pallidus. In general, these changes in neuronal activity lasted longer than EMG activity associated with reaching. The proportions of neurons activated were significantly larger in the putamen than the caudate nucleus. In the pallidum, the proportions were not statistically different from either the putamen or caudate nucleus, and no significant difference was found between the internal and external pallidal segments. Significant selectivity for movements to different targets was observed in 36% of neurons in the putamen, 28% in the caudate nucleus and 9% in the globus pallidus. The lower proportion in the globus pallidus compared to the striatum was significant (P < 0.002). Clusters of activated neurons were found in the striatum, however, the timing of changes was often different for individual neurons in these clusters. A cross-correlation analysis of the activity of neurons in the clusters revealed no evidence of common inputs, suggesting that striatal neurons in close proximity with neurons showing similar changes in activity are driven by different populations of neurons. In the putamen, the anatomical locations of neurons with changes in activity related to movement execution were on average significantly more posterior and lateral than neurons with changes related to the preparation of movement described earlier. These findings support the view that the putamen and the caudate nucleus contain distinct functional areas. The present studies show that most anatomical regions in both the striatum and pallidum participate in the control of executing reaching movements.

Channel Density Distributions Explain Spiking Variability in the Globus Pallidus: A Combined Physiology and Computer Simulation Database Approach

Globus pallidus (GP) neurons recorded in brain slices show significant variability in intrinsic electrophysiological properties. To investigate how this variability arises, we manipulated the biophysical properties of GP neurons using computer simulations. Specifically, we created a GP neuron model database with 100,602 models that had varying densities of nine membrane conductances centered on a hand-tuned model that replicated typical physiological data. To test the hypothesis that the experimentally observed variability can be attributed to variations in conductance densities, we compared our model database results to a physiology database of 146 slice recordings. The electrophysiological properties of generated models and recordings were assessed with identical current injection protocols and analyzed with a uniform set of measures, allowing a systematic analysis of the effects of varying voltage-gated and calcium-gated conductance densities on the measured properties and a detailed comparison between models and recordings. Our results indicated that most of the experimental variability could be matched by varying conductance densities, which we confirmed with additional partial block experiments. Further analysis resulted in two key observations: (1) each voltage-gated conductance had effects on multiple measures such as action potential waveform and spontaneous or stimulated spike rates; and (2) the effect of each conductance was highly dependent on the background context of other conductances present. In some cases, such interactions could reverse the effect of the density of one conductance on important excitability measures. This context dependence of conductance density effects is important to understand drug and neuromodulator effects that work by affecting ion channels.

Primate basal ganglia activity in a precued reaching task: preparation for movement

Single cell activity was recorded from the primate putamen, caudate nucleus, and globus pallidus during a precued reaching movement task. Two monkeys were trained to touch one of several target knobs mounted in front of them after an LED was lighted on the correct target. A precue was presented prior to this target “go cue” by a randomly varied delay interval, giving the animals partial or complete advance information about the target for the movement task. The purpose of this design was to examine neuronal activity in the major structures of the basal ganglia during the preparation phase of limb movements when varying amounts of advance information were provided to the animals. The reaction times were shortest with complete precues, intermediate with partial precues, and longest with precues containing no information, demonstrating that the animals used precue information to prepare partly or completely for the reaching movement before the target go cue was given. Changes in activity were seen in the basal ganglia during the preparatory period in 30% of neurons in putamen, 31% in caudate nucleus, and 27% in globus pallidus. Preparatory changes were stronger and more closely linked to the time of movement initiation in putamen than in caudate nucleus. Although the amount of information contained in the precues had no significant effect on preparatory activity preceding the target go cue, a directional selectivity during this period was observed for a subset of neurons with preparatory changes (15% in putamen, 11% in caudate nucleus, 14% in globus pallidus) when the precue contained information about the upcoming direction of movement. A smaller subset of neurons showed selectivity for the preparation of movement amplitude. A larger number of preparatory changes showed selectivity for the direction or amplitude of movement following the target go cue than in the delay period before the cue. The intensity of preparatory changes in activity in many cases depended on the length of the delay interval preceding the target go cue. Even following the target go cue, the intensity of the preparatory changes in activity continued to be significantly influenced by the length of the preceding delay interval for 11% of changes in putamen, 8% in caudate nucleus, and 18% in globus pallidus. This finding suggests that preparatory activity in the basal ganglia takes part in a process termed motor readiness. Behaviorally, this process was seen as a shortening of reaction time regardless of precue information for trials in which the delay interval was long and the animals showed an increased readiness to move. Preparatory activity in putamen following the target go cue was most intense in trials with a short delay interval, in which motor readiness had not achieved its maximum level prior to the go cue. The results of this study indicate that the basal ganglia are involved in multiple aspects of preparatory processing for limb movement. Preparatory processing is therefore unlikely to be divided anatomically along the functional lines examined in this study. In the basal ganglia, preparatory processing reflects both preparation for target selection and control of timing the onset of movement (motor readiness). These characteristics can be integrated in a functional scheme in which the basal ganglia are predominantly responsible for the automated execution of well-trained behavior.

Neural correlates of time-varying functional connectivity in the rat

Functional connectivity between brain regions, measured with resting state functional magnetic resonance imaging, holds great potential for understanding the basis of behavior and neuropsychiatric diseases. Recently it has become clear that correlations between the blood oxygenation level dependent (BOLD) signals from different areas vary over the course of a typical scan (6-10 min in length), though the changes are obscured by standard methods of analysis that assume the relationships are stationary. Unfortunately, because similar variability is observed in signals that share no temporal information, it is unclear which dynamic changes are related to underlying neural events. To examine this question, BOLD data were recorded simultaneously with local field potentials (LFP) from interhemispheric primary somatosensory cortex (SI) in anesthetized rats. LFP signals were converted into band-limited power (BLP) signals including delta, theta, alpha, beta and gamma. Correlation between signals from interhemispheric SI was performed in sliding windows to produce signals of correlation over time for BOLD and each BLP band. Both BOLD and BLP signals showed large changes in correlation over time and the changes in BOLD were significantly correlated to the changes in BLP. The strongest relationship was seen when using the theta, beta and gamma bands. Interestingly, while steady-state BOLD and BLP correlate with the global fMRI signal, dynamic BOLD becomes more like dynamic BLP after the global signal is regressed. As BOLD sliding window connectivity is partially reflecting underlying LFP changes, the present study suggests it may be a valuable method of studying dynamic changes in brain states.

The Contribution of NMDA and AMPA Conductances to the Control of Spiking in Neurons of the Deep Cerebellar Nuclei

We performed whole-cell patch-clamp recordings in vitro to investigate the integration of excitatory and inhibitory inputs in neurons of the deep cerebellar nuclei (DCN) by applying synthetic synaptic input patterns with dynamic clamping. We explored an input regime in which excitation and inhibition had an ongoing baseline rate because both input pathways show ongoing activity in vivo. We found that spiking was time-locked to transients in the inputs, consisting of brief decreases in inhibitory or increases in excitatory conductance. Such input transients were caused by synchronization among multiple inputs. However, we found that temporal synchrony in the inhibitory input pathway had preferential access to the control of DCN spiking, because the large NMDA component of the excitatory inputs smoothed out temporal transients in this pathway. Thus, synaptic integration in the DCN appears to be tuned to allow the cerebellar cortical output from Purkinje cells preferential access to the control of DCN spiking. The effect of temporal modulations in the inhibition was further enhanced by the voltage dependence of the NMDA inputs. Thus, the presence of a baseline of mossy and climbing fiber inputs boosted depolarizing responses caused by reduced inhibition by the voltage-dependent increase in inward NMDA current. Overall, our results show that correlated activity or pauses in populations of Purkinje cells are well suited to the dynamic control of DCN spiking. In addition, strong transients in excitation can directly drive DCN responses that bypass cerebellar cortical processing.

Sodium channels and dendritic spike initiation at excitatory synapses in globus pallidus neurons.

Glutamatergic inputs from the subthalamic nucleus are suspected to provide a prominent source of excitation to globus pallidus (GP) neurons, despite their scarce number and mainly distal dendritic location. In this study we address the issue of whether dendritic sodium channels may facilitate the effect of excitatory inputs in GP. First, we examined the subcellular distribution of sodium channels using electron microscopic observations of immunoperoxidase and immunogold labeling. Voltage-gated sodium channels were found throughout GP dendrites and furthermore exhibited a specific clustering at sites of excitatory synaptic inputs. To examine the possibility that these channels could mediate dendritic spike generation, synaptic stimulation at visualized dendritic sites was performed during whole-cell recordings in vitro. These recordings revealed dendritic spike initiation in response to small excitatory inputs even for very distal stimulation sites. In contrast, subthreshold responses were mostly or fully attenuated at the soma for stimulation sites on distal dendrites. Computer simulations support the hypothesis that postsynaptic clustering of sodium channels allows dendritic triggering of spikes in response to inputs that would be too small to trigger a spike given uniformly distributed dendritic sodium channels. These findings indicate that postsynaptic sodium channel clustering is an effective mechanism to mediate a novel form of synaptic amplification and dendritic spike initiation. The ability of small amounts of excitation to trigger spikes in GP dendrites supports the prominent role of subthalamic input in the control of GP activity.

Broadband Local Field Potentials Correlate with Spontaneous Fluctuations in Functional Magnetic Resonance Imaging Signals in the Rat Somatosensory Cortex Under Isoflurane Anesthesia

Resting-state functional magnetic resonance imaging (fMRI) is widely used for exploring spontaneous brain activity and large-scale networks; however, the neural processes underlying the observed resting-state fMRI signals are not fully understood. To investigate the neural correlates of spontaneous low-frequency fMRI fluctuations and functional connectivity, we developed a rat model of simultaneous fMRI and multiple-site intracortical neural recordings. This allowed a direct comparison to be made between the spontaneous signals and interhemispheric connectivity measured with the two modalities. Results show that low-frequency blood oxygen level-dependent (BOLD) fluctuations (<0.1 Hz) correlate significantly with slow power modulations (<0.1 Hz) of local field potentials (LFPs) in a broad frequency range (1-100 Hz) under isoflurane anesthesia (1%-1.8%). Peak correlation occurred between neural and hemodynamic activity when the BOLD signal was delayed by ~4 sec relative to the LFP signal. The spatial location and extent of correlation was highly reproducible across studies, with the maximum correlation localized to a small area surrounding the site of microelectrode recording and to the homologous area in the contralateral hemisphere for most rats. Interhemispheric connectivity was calculated using BOLD correlation and band-limited LFP (1-4, 4-8, 8-14, 14-25, 25-40, and 40-100 Hz) coherence. Significant coherence was observed for the slow power changes of all LFP frequency bands as well as in the low-frequency BOLD data. A preliminary investigation of the effect of anesthesia on interhemispheric connectivity indicates that coherence in the high-frequency LFP bands declines with increasing doses of isoflurane, whereas coherence in the low-frequency LFP bands and the BOLD signal increases. These findings suggest that resting-state fMRI signals might be a reflection of broadband LFP power modulation, at least in isoflurane-anesthetized rats.