Faculty Bibliography

Network oscillations support transient communication across brain structures. We show here, in rats, that task-related neuronal activity in the medial prefrontal cortex (PFC), the hippocampus, and the ventral tegmental area (VTA), regions critical for working memory, is coordinated by a 4 Hz oscillation. A prominent increase of power and coherence of the 4 Hz oscillation in the PFC and the VTA and its phase modulation of gamma power in both structures was present in the working memory part of the task. Subsets of both PFC and hippocampal neurons predicted the turn choices of the rat. The goal-predicting PFC pyramidal neurons were more strongly phase locked to both 4 Hz and hippocampal theta oscillations than nonpredicting cells. The 4 Hz and theta oscillations were phase coupled and jointly modulated both gamma waves and neuronal spikes in the PFC, the VTA, and the hippocampus. Thus, multiplexed timing mechanisms in the PFC-VTA-hippocampus axis may support processing of information, including working memory

Hippocampal CA1 pyramidal neurons have frequently been regarded as a homogeneous cell population in biophysical, pharmacological and modeling studies. We found robust differences between pyramidal neurons residing in the deep and superficial CA1 sublayers in rats. Compared with their superficial peers, deep pyramidal cells fired at higher rates, burst more frequently, were more likely to have place fields and were more strongly modulated by slow oscillations of sleep. Both deep and superficial pyramidal cells fired preferentially at the trough of theta oscillations during maze exploration, whereas deep pyramidal cells shifted their preferred phase of firing to the peak of theta during rapid eye movement (REM) sleep. Furthermore, although the majority of REM theta phase-shifting cells fired at the ascending phase of gamma oscillations during waking, nonshifting cells preferred the trough. Thus, CA1 pyramidal cells in adjacent sublayers can address their targets jointly or differentially, depending on brain states

Hippocampal sharp waves (SPWs) and associated fast ('ripple') oscillations (SPW-Rs) in the CA1 region are among the most synchronous physiological patterns in the mammalian brain. Using two-dimensional arrays of electrodes for recording local field potentials and unit discharges in freely moving rats, we studied the emergence of ripple oscillations (140-220 Hz) and compared their origin and cellular-synaptic mechanisms with fast gamma oscillations (90-140 Hz). We show that (1) hippocampal SPW-Rs and fast gamma oscillations are quantitatively distinct patterns but involve the same networks and share similar mechanisms; (2) both the frequency and magnitude of fast oscillations are positively correlated with the magnitude of SPWs; (3) during both ripples and fast gamma oscillations the frequency of network oscillation is higher in CA1 than in CA3; and (4) the emergence of CA3 population bursts, a prerequisite for SPW-Rs, is biased by activity patterns in the dentate gyrus and entorhinal cortex, with the highest probability of ripples associated with an 'optimum' level of dentate gamma power. We hypothesize that each hippocampal subnetwork possesses distinct resonant properties, tuned by the magnitude of the excitatory drive

Axonal arbors of principal neurons form the backbone of neuronal networks in the mammalian cortex. Three-dimensional reconstructions of complete axonal trees are invaluable for quantitative analysis and modeling. However, digital data are still sparse due to labor intensity of reconstructing these complex structures. We augmented conventional tracing techniques with computational approaches to reconstruct fully labeled axonal morphologies. We digitized the axons of three rat hippocampal pyramidal cells intracellularly filled in vivo from different CA3 sub-regions: two from areas CA3b and CA3c, respectively, toward the septal pole, and one from the posterior/ventral area (CA3pv) near the temporal pole. The reconstruction system was validated by comparing the morphology of the CA3c neuron with that traced from the same cell by a different operator on a standard commercial setup. Morphometric analysis revealed substantial differences among neurons. Total length ranged from 200 (CA3b) to 500 mm (CA3c), and axonal branching complexity peaked between 1 (CA3b and CA3pv) and 2 mm (CA3c) of Euclidean distance from the soma. Length distribution was analyzed among sub-regions (CA3a,b,c and CA1a,b,c), cytoarchitectonic layers, and longitudinal extent within a three-dimensional template of the rat hippocampus. The CA3b axon extended thrice more collaterals within CA3 than into CA1. On the contrary, the CA3c projection was double into CA1 than within CA3. Moreover, the CA3b axon extension was equal between strata oriens and radiatum, while the CA3c axon displayed an oriens/radiatum ratio of 1:6. The axonal distribution of the CA3pv neuron was intermediate between those of the CA3b and CA3c neurons both relative to sub-regions and layers, with uniform collateral presence across CA3/CA1 and moderate preponderance of radiatum over oriens. In contrast with the dramatic sub-region and layer differences, the axon longitudinal spread around the soma was similar for the three neurons. To fully characterize the axonal diversity of CA3 principal neurons will require higher-throughput reconstruction systems beyond the threefold speed-up of the method adopted here

Hippocampal neurons can display reliable and long-lasting sequences of transient firing patterns, even in the absence of changing external stimuli. We suggest that time-keeping is an important function of these sequences, and propose a network mechanism for their generation. We show that sequences of neuronal assemblies recorded from rat hippocampal CA1 pyramidal cells can reliably predict elapsed time (15-20 s) during wheel running with a precision of 0.5 s. In addition, we demonstrate the generation of multiple reliable, long-lasting sequences in a recurrent network model. These sequences are generated in the presence of noisy, unstructured inputs to the network, mimicking stationary sensory input. Identical initial conditions generate similar sequences, whereas different initial conditions give rise to distinct sequences. The key ingredients responsible for sequence generation in the model are threshold-adaptation and a Mexican-hat-like pattern of connectivity among pyramidal cells. This pattern may arise from recurrent systems such as the hippocampal CA3 region or the entorhinal cortex. We hypothesize that mechanisms that evolved for spatial navigation also support tracking of elapsed time in behaviorally relevant contexts

Glucose is the primary energetic substrate of the brain, and measurements of its metabolism are the basis of major functional cerebral imaging methods. Contrary to the general view that neurons are fueled solely by glucose in proportion to their energetic needs, recent in vitro and ex vivo analyses suggest that glucose preferentially feeds astrocytes. However, the cellular fate of glucose in the intact brain has not yet been directly observed. We have used a real-time method for measuring glucose uptake in astrocytes and neurons in vivo in male rats by imaging the trafficking of the nonmetabolizable glucose analog 6-deoxy-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-aminoglucose (6-NBDG) using two-photon microscopy. During resting conditions we found that astrocytes and neurons both take up 6-NBDG at the same rate in the barrel cortex of the rat. However, during intense neuronal activity triggered by whisker stimulation, astrocytes rapidly accelerated their uptake, whereas neuronal uptake remained almost unchanged. After the stimulation period, astrocytes returned to their preactivation rates of uptake paralleling the neuronal rate of uptake. These observations suggest that glucose is taken up primarily by astrocytes, supporting the view that functional imaging experiments based on glucose analogs extraction may predominantly reflect the metabolic activity of the astrocytic network

A widely discussed hypothesis in neuroscience is that transiently active ensembles of neurons, known as 'cell assemblies,' underlie numerous operations of the brain, from encoding memories to reasoning. However, the mechanisms responsible for the formation and disbanding of cell assemblies and temporal evolution of cell assembly sequences are not well understood. I introduce and review three interconnected topics, which could facilitate progress in defining cell assemblies, identifying their neuronal organization, and revealing causal relationships between assembly organization and behavior. First, I hypothesize that cell assemblies are best understood in light of their output product, as detected by 'reader-actuator' mechanisms. Second, I suggest that the hierarchical organization of cell assemblies may be regarded as a neural syntax. Third, constituents of the neural syntax are linked together by dynamically changing constellations of synaptic weights ('synapsembles'). The existing support for this tripartite framework is reviewed and strategies for experimental testing of its predictions are discussed

Low intensity electric fields have been suggested to affect the ongoing neuronal activity in vitro and in human studies. However, the physiological mechanism of how weak electrical fields affect and interact with intact brain activity is not well understood. We performed in vivo extracellular and intracellular recordings from the neocortex and hippocampus of anesthetized rats and extracellular recordings in behaving rats. Electric fields were generated by sinusoid patterns at slow frequency (0.8, 1.25 or 1.7 Hz) via electrodes placed on the surface of the skull or the dura. Transcranial electric stimulation (TES) reliably entrained neurons in widespread cortical areas, including the hippocampus. The percentage of TES phase-locked neurons increased with stimulus intensity and depended on the behavioral state of the animal. TES-induced voltage gradient, as low as 1 mV/mm at the recording sites, was sufficient to phase-bias neuronal spiking. Intracellular recordings showed that both spiking and subthreshold activity were under the combined influence of TES forced fields and network activity. We suggest that TES in chronic preparations may be used for experimental and therapeutic control of brain activity

A thorough knowledge of the intrinsic circuit properties of the entorhinal cortex (EC) and the temporal dynamics these circuits support is essential for understanding how information is exchanged between the hippocampus and neocortex. Using intracellular and extracellular recordings in the anesthetized rat and anatomical reconstruction of single cells, we found that EC5 and EC2 principal neurons form large axonal networks mainly within their layers, interconnected by the more vertically organized axon trees of EC3 pyramidal cells. Principal cells showed layer-specific unique membrane properties and contributed differentially to theta and gamma oscillations. EC2 principal cells were most strongly phase modulated by EC theta. The multiple gamma oscillators, present in the various EC layers, were temporally coordinated by the phase of theta waves. Putative interneurons in all EC layers fired relatively synchronously within the theta cycle, coinciding with the maximum power of gamma oscillation. The special wiring architecture and unique membrane properties of EC neurons may underlie their behaviorally distinct firing patterns in the waking animal

Recordings of large neuronal ensembles and neural stimulation of high spatial and temporal precision are important requisites for studying the real-time dynamics of neural networks. Multiple-shank silicon probes enable large-scale monitoring of individual neurons. Optical stimulation of genetically targeted neurons expressing light-sensitive channels or other fast (milliseconds) actuators offers the means for controlled perturbation of local circuits. Here we describe a method to equip the shanks of silicon probes with micron-scale light guides for allowing the simultaneous use of the two approaches. We then show illustrative examples of how these compact hybrid electrodes can be used in probing local circuits in behaving rats and mice. A key advantage of these devices is the enhanced spatial precision of stimulation that is achieved by delivering light close to the recording sites of the probe. When paired with the expression of light-sensitive actuators within genetically specified neuronal populations, these devices allow the relatively straightforward and interpretable manipulation of network activity