Lateral and feedforward inhibition suppress asynchronous activity in a large, biophysically-detailed computational model of the striatal network.

Striatal medium spiny neurons (MSNs) receive lateral inhibitory projections from other MSNs and feedforward inhibitory projections from fast-spiking, parvalbumin-containing striatal interneurons (FSIs). The functional roles of these connections are unknown, and difficult to study in an experimental preparation. We therefore investigated the functionality of both lateral (MSN-MSN) and feedforward (FSI-MSN) inhibition using a large-scale computational model of the striatal network. The model consists of 2744 MSNs comprised of 189 compartments each and 121 FSIs comprised of 148 compartments each, with dendrites explicitly represented and almost all known ionic currents included and strictly constrained by biological data as appropriate. Our analysis of the model indicates that both lateral inhibition and feedforward inhibition function at the population level to limit non-ensemble MSN spiking while preserving ensemble MSN spiking. Specifically, lateral inhibition enables large ensembles of MSNs firing synchronously to strongly suppress non-ensemble MSNs over a short time-scale (10-30 ms). Feedforward inhibition enables FSIs to strongly inhibit weakly activated, non-ensemble MSNs while moderately inhibiting activated ensemble MSNs. Importantly, FSIs appear to more effectively inhibit MSNs when FSIs fire asynchronously. Both types of inhibition would increase the signal-to-noise ratio of responding MSN ensembles and contribute to the formation and dissolution of MSN ensembles in the striatal network.

Ketamine disrupts θ modulation of γ in a computer model of hippocampus.

Abnormalities in oscillations have been suggested to play a role in schizophrenia. We studied theta-modulated gamma oscillations in a computer model of hippocampal CA3 in vivo with and without simulated application of ketamine, an NMDA receptor antagonist and psychotomimetic. Networks of 1200 multicompartment neurons [pyramidal, basket, and oriens-lacunosum moleculare (OLM) cells] generated theta and gamma oscillations from intrinsic network dynamics: basket cells primarily generated gamma and amplified theta, while OLM cells strongly contributed to theta. Extrinsic medial septal inputs paced theta and amplified both theta and gamma oscillations. Exploration of NMDA receptor reduction across all location combinations demonstrated that the experimentally observed ketamine effect occurred only with isolated reduction of NMDA receptors on OLMs. In the ketamine simulations, lower OLM activity reduced theta power and disinhibited pyramidal cells, resulting in increased basket cell activation and gamma power. Our simulations predict the following: (1) ketamine increases firing rates; (2) oscillations can be generated by intrinsic hippocampal circuits; (3) medial-septum inputs pace and augment oscillations; (4) pyramidal cells lead basket cells at the gamma peak but lag at trough; (5) basket cells amplify theta rhythms; (6) ketamine alters oscillations due to primary blockade at OLM NMDA receptors; (7) ketamine alters phase relationships of cell firing; (8) ketamine reduces network responsivity to the environment; (9) ketamine effect could be reversed by providing a continuous inward current to OLM cells. We suggest that this last prediction has implications for a possible novel treatment for cognitive deficits of schizophrenia by targeting OLM cells.

Ketamine modulates theta and gamma oscillations.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor glutamatergic antagonist, has been studied as a model of schizophrenia when applied in subanesthetic doses. In EEG studies, ketamine affects sensory gating and alters the oscillatory characteristics of neuronal signals in a complex manner. We investigated the effects of ketamine on in vivo recordings from the CA3 region of mouse hippocampus referenced to the ipsilateral frontal sinus using a paired-click auditory gating paradigm. One issue of particular interest was elucidating the effect of ketamine on background network activity, poststimulus evoked and induced activity. We find that ketamine attenuates the theta frequency band in both background activity and in poststimulus evoked activity. Ketamine also disrupts a late, poststimulus theta power reduction seen in control recordings. In the gamma frequency range, ketamine enhances both background and evoked power, but decreases relative induced power. These findings support a role for NMDA receptors in mediating the balance between theta and gamma responses to sensory stimuli, with possible implications for dysfunction in schizophrenia.

Sublinear summation of afferent inputs to the nucleus accumbens in the awake rat.

The mechanisms by which the nucleus accumbens integrates afferent input from limbic and cortical structures have been influential in the development of models of psychiatric disorders such as schizophrenia. Previous studies of the response of nucleus accumbens (Nacb) cells to the stimulation of afferent inputs from hippocampus (HC) and prefrontal cortex (PFC) have demonstrated that PFC throughput can be modulated by preceding HC input. Examination of the post-synaptic potential size has suggested, however, that summation of these inputs is sublinear. All studies to date examining Nacb integration of inputs via stimulation of afferents have been performed in the anaesthetized rat. The present experiments compare the response of Nacb cells to different combinations of PFC and HC stimulation in awake and isoflurane-anaesthetized rats that were chronically implanted with both stimulating and recording electrodes. The results of these experiments suggest that summation of afferent input in the Nacb of the awake rat is predominantly sublinear, with only a minority of neurons demonstrating modulation of PFC inputs by the HC in the awake or the anaesthetized animal. The response profile of many cells changed during anaesthesia when compared to the awake condition, and on average showed suppression to PFC input 50 and 150 ms following HC stimulation while under deep isoflurane anaesthesia. These results suggest that sublinear integration of afferent input from the PFC and HC is the dominant mode of integration of Nacb cells in the awake animal, which has implications for corticostriatal models of psychiatric dysfunction.

Sensitivity to motion features in point light displays of biological motion.

Psychophysical experiments are described that measure the sensitivity to motion features in point light displays of biological motion. Three motion features were investigated: the relative motion of the thighs, the relative motion of the thigh and leg, and the velocity profile of the leg. The perceptual threshold for discriminating a change in each motion feature was compared in upright and inverted point light displays. We find that subjects are more sensitive to two of the motion features in the upright display configuration (relative motion of thighs, relative motion of thigh and leg), but more sensitive to the third feature (velocity profile of the leg) in the inverted configuration. We propose that perceptual sensitivity to features used in biological motion perception should be greater in upright versus inverted displays. The results suggest that motion features differ in salience in biological motion perception.

Effects of dopaminergic modulation on the integrative properties of the ventral striatal medium spiny neuron.

Dopaminergic modulation produces a variety of functional changes in the principal cell of the striatum, the medium spiny neuron (MSN). Using a 189-compartment computational model of a ventral striatal MSN, we simulated whole cell D1- and D2-receptor-mediated modulation of both intrinsic (sodium, calcium, and potassium) and synaptic currents (AMPA and NMDA). Dopamine (DA) modulations in the model were based on a review of published experiments in both ventral and dorsal striatum. To objectively assess the net effects of DA modulation, we combined reported individual channel modulations into either D1- or D2-receptor modulation conditions and studied them separately. Contrary to previous suggestions, we found that D1 modulation had no effect on MSN nonlinearity and could not induce bistability. In agreement with previous suggestions, we found that dopaminergic modulation leads to changes in input filtering and neuronal excitability. Importantly, the changes in neuronal excitability agree with the classical model of basal ganglia function. We also found that DA modulation can alter the integration time window of the MSN. Interestingly, the effects of DA modulation of synaptic properties opposed the effects of DA modulation of intrinsic properties, with the synaptic modulations generally dominating the net effect. We interpret this lack of synergy to suggest that the regulation of whole cell integrative properties is not the primary functional purpose of DA. We suggest that D1 modulation might instead primarily regulate calcium influx to dendritic spines through NMDA and L-type calcium channels, by both direct and indirect mechanisms.

Shape representation by a network of V4-like cells.

Cells in extrastriate visual cortex have been reported to be selective for various configurations of local contour shape [Pasupathy, A., & Connor, C. E. (2001). Shape representation in area V4: Position-specific tuning for boundary conformation. The Journal of Neurophysiology, 86 (5), 2505-2519; Hegdé, J., & Van Essen, D. C. (2003). Strategies of shape representation in macaque visual area V2. Visual Neuroscience, 20 (3), 313-328]. Specifically, Pasupathy and Connor found that in area V4 most cells are strongly responsive to a particular local contour conformation located at a specific position on the object's boundary. We used a population of "V4-like cells"-units sensitive to multiple shape features modeled after V4 cell behavior-to generate representations of different shapes. Standard classification algorithms (earth mover's distance, support vector machines) applied to this population representation demonstrate high recognition accuracies classifying handwritten digits in the MNIST database and objects in the MPEG-7 Shape Silhouette database. We compare the performance of the V4-like unit representation to the "shape context" representation of Belongie et al. [Belongie, S., Malik, J., & Puzicha, J. (2002). Shape matching and object recognition using shape contexts. IEEE Transactions on Pattern Analysis and Machine Intelligence, 24 (24), 509-522]. Results show roughly comparable recognition accuracies using the two representations when tested on portions of the MNIST database. We analyze the relative contributions of various V4-like feature sensitivities to recognition accuracy and robustness to noise - feature sensitivities include curvature magnitude, direction of curvature, global orientation of the contour segment, distance of the contour segment from object center, and modulatory effect of adjacent contour regions. Among these, local curvature appears to be the most informative variable for shape recognition. Our results support the hypothesis that V4 cells function as robust shape descriptors in the early stages of object recognition.

Implementation of dual simultaneous microelectrode recording systems during deep brain stimulation surgery for Parkinson's disease: technical note.

OBJECTIVE: Microelectrode recording during deep brain stimulation surgery improves the likelihood of successful target localization and enables the electrophysiological characterization of human neural structures. Many clinical recording systems do not support the ability to capture research-quality recordings. Established clinical centers already using such equipment may be prevented from acquiring human intracranial data because of the need to completely change recording systems to obtain research-quality recordings. This technical note describes the novel design and implementation of a recording system that significantly improves research capabilities without disrupting the existing clinical setup. METHODS: This design introduces a second recording system (including pre-amplifier, differential amplifier, analog-to-digital converter, and computer with analysis software) that divides the microelectrode signal into two independent streams. RESULTS: This design preserves the existing intraoperative recording setup, but significantly improves research-level recording, data storage, and analysis capabilities. CONCLUSION: We provide the first description of such a system using components that are all commercially available and relatively inexpensive. This approach presents an appealing alternative to the purchase of an entirely new system for surgical teams that already perform intraoperative recordings to assist in stereotactic target localization, yet wish to expand their neurophysiological recording capabilities.

NMDA/AMPA ratio impacts state transitions and entrainment to oscillations in a computational model of the nucleus accumbens medium spiny projection neuron.

We describe a computational model of the principal cell in the nucleus accumbens (NAcb), the medium spiny projection (MSP) neuron. The model neuron, constructed in NEURON, includes all of the known ionic currents in these cells and receives synaptic input from simulated spike trains via NMDA, AMPA, and GABAA receptors. After tuning the model by adjusting maximal current conductances in each compartment, the model cell closely matched whole-cell recordings from an adult rat NAcb slice preparation. Synaptic inputs in the range of 1000-1300 Hz are required to maintain an "up" state in the model. Cell firing in the model required concurrent depolarization of several dendritic branches, which responded independently to afferent input. Depolarization from action potentials traveled to the tips of the dendritic branches and increased Ca2+ influx through voltage-gated Ca2+ channels. As NMDA/AMPA current ratios were increased, the membrane showed an increase in hysteresis of "up" and "down" state dwell times, but intrinsic bistability was not observed. The number of oscillatory inputs required to entrain the model cell was determined to be approximately 20% of the "up" state inputs. Altering the NMDA/AMPA ratio had a profound effect on processing of afferent input, including the ability to entrain to oscillations in afferent input in the theta range (4-12 Hz). These results suggest that afferent information integration by the NAcb MSP cell may be compromised by pathology in which the NMDA current is altered or modulated, as has been proposed in both schizophrenia and addiction.

Principal component analysis of temporal and spatial information for human gait recognition.

Principal component analysis was applied to human gait patterns to investigate the role and relative importance of temporal versus spatial features. Datasets consisted of various limb and body angles sampled over increasingly long time intervals. We find that spatial and temporal cues may be useful for different aspects of recognition. Temporal cues contain information that can distinguish the phase of the gait cycle; spatial cues are useful for distinguishing running from walking. PCA and related techniques may be useful for identifying features used by the visual system for recognizing biological motion.