The Unexplored Territory of Neural Models: Potential Guides for Exploring the Function of Metabotropic Neuromodulation.

The space of possible neural models is enormous and under-explored. Single cell computational neuroscience models account for a range of dynamical properties of membrane potential, but typically do not address network function. In contrast, most models focused on network function address the dimensions of excitatory weight matrices and firing thresholds without addressing the complexities of metabotropic receptor effects on intrinsic properties. There are many under-explored dimensions of neural parameter space, and the field needs a framework for representing what has been explored and what has not. Possible frameworks include maps of parameter spaces, or efforts to categorize the fundamental elements and molecules of neural circuit function. Here we review dimensions that are under-explored in network models that include the metabotropic modulation of synaptic plasticity and presynaptic inhibition, spike frequency adaptation due to calcium-dependent potassium currents, and afterdepolarization due to calcium-sensitive non-specific cation currents and hyperpolarization activated cation currents. Neuroscience research should more effectively explore possible functional models incorporating under-explored dimensions of neural function.

Interneuronal mechanisms of hippocampal theta oscillations in a full-scale model of the rodent CA1 circuit.

The hippocampal theta rhythm plays important roles in information processing; however, the mechanisms of its generation are not well understood. We developed a data-driven, supercomputer-based, full-scale (1:1) model of the rodent CA1 area and studied its interneurons during theta oscillations. Theta rhythm with phase-locked gamma oscillations and phase-preferential discharges of distinct interneuronal types spontaneously emerged from the isolated CA1 circuit without rhythmic inputs. Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation. These simulations reveal new insights into the spatiotemporal organization of the CA1 circuit during theta oscillations.

Target-selectivity of parvalbumin-positive interneurons in layer II of medial entorhinal cortex in normal and epileptic animals.

The medial entorhinal cortex layer II (MEClayerII ) is a brain region critical for spatial navigation and memory, and it also demonstrates a number of changes in patients with, and animal models of, temporal lobe epilepsy (TLE). Prior studies of GABAergic microcircuitry in MEClayerII revealed that cholecystokinin-containing basket cells (CCKBCs) select their targets on the basis of the long-range projection pattern of the postsynaptic principal cell. Specifically, CCKBCs largely avoid reelin-containing principal cells that form the perforant path to the ipsilateral dentate gyrus and preferentially innervate non-perforant path forming calbindin-containing principal cells. We investigated whether parvalbumin containing basket cells (PVBCs), the other major perisomatic targeting GABAergic cell population, demonstrate similar postsynaptic target selectivity as well. In addition, we tested the hypothesis that the functional or anatomic arrangement of circuit selectivity is disrupted in MEClayerII in chronic TLE, using the repeated low-dose kainate model in rats. In control animals, we found that PVBCs innervated both principal cell populations, but also had significant selectivity for calbindin-containing principal cells in MEClayerII . However, the magnitude of this preference was smaller than for CCKBCs. In addition, axonal tracing and paired recordings showed that individual PVBCs were capable of contacting both calbindin and reelin-containing principal cells. In chronically epileptic animals, we found that the intrinsic properties of the two principal cell populations, the GABAergic perisomatic bouton numbers, and selectivity of the CCKBCs and PVBCs remained remarkably constant in MEClayerII . However, miniature IPSC frequency was decreased in epilepsy, and paired recordings revealed the presence of direct excitatory connections between principal cells in the MEClayerII in epilepsy, which is unusual in normal adult MEClayerII . Taken together, these findings advance our knowledge about the organization of perisomatic inhibition both in control and in epileptic animals. © 2015 Wiley Periodicals, Inc.

Proton radiation alters intrinsic and synaptic properties of CA1 pyramidal neurons of the mouse hippocampus.

High-energy protons constitute at least 85% of the fluence of energetic ions in interplanetary space. Although protons are only sparsely ionizing compared to higher atomic mass ions, they nevertheless significantly contribute to the delivered dose received by astronauts that can potentially affect central nervous system function at high fluence, especially during prolonged deep space missions such as to Mars. Here we report on the long-term effects of 1 Gy proton irradiation on electrophysiological properties of CA1 pyramidal neurons in the mouse hippocampus. The hippocampus is a key structure for the formation of long-term episodic memory, for spatial orientation and for information processing in a number of other cognitive tasks. CA1 pyramidal neurons form the last and critical relay point in the trisynaptic circuit of the hippocampal principal neurons through which information is processed before being transferred to other brain areas. Proper functioning of CA1 pyramidal neurons is crucial for hippocampus-dependent tasks. Using the patch-clamp technique to evaluate chronic effects of 1 Gy proton irradiation on CA1 pyramidal neurons, we found that the intrinsic membrane properties of CA1 pyramidal neurons were chronically altered at 3 months postirradiation, resulting in a hyperpolarization of the resting membrane potential (VRMP) and a decrease in input resistance (Rin). These small but significant alterations in intrinsic properties decreased the excitability of CA1 pyramidal neurons, and had a dramatic impact on network function in a computational model of the CA1 microcircuit. We also found that proton-radiation exposure upregulated the persistent Na(+) current (INaP) and increased the rate of miniature excitatory postsynaptic currents (mEPSCs). Both the INaP and the heightened rate of mEPSCs contribute to neuronal depolarization and excitation, and at least in part, could compensate for the reduced excitability resulting from the radiation effects on the VRMP and the Rin. These results show long-term alterations in the intrinsic properties of CA1 pyramidal cells after realistic, low-dose proton irradiation.

Functional fission of parvalbumin interneuron classes during fast network events.

Fast spiking, parvalbumin (PV) expressing hippocampal interneurons are classified into basket, axo-axonic (chandelier), and bistratified cells. These cell classes play key roles in regulating local circuit operations and rhythmogenesis by releasing GABA in precise temporal patterns onto distinct domains of principal cells. In this study, we show that each of the three major PV cell classes further splits into functionally distinct sub-classes during fast network events in vivo. During the slower (<10 Hz) theta oscillations, each cell class exhibited its own characteristic, relatively uniform firing behavior. However, during faster (>90 Hz) oscillations, within-class differences in PV interneuron discharges emerged, which segregated along specific features of dendritic structure or somatic location. Functional divergence of PV sub-classes during fast but not slow network oscillations effectively doubles the repertoire of spatio-temporal patterns of GABA release available for rapid circuit operations.

Parvalbumin-positive basket cells differentiate among hippocampal pyramidal cells.

CA1 pyramidal cells (PCs) are not homogeneous but rather can be grouped by molecular, morphological, and functional properties. However, less is known about synaptic sources differentiating PCs. Using paired recordings in vitro, two-photon Ca(2+) imaging in vivo, and computational modeling, we found that parvalbumin-expressing basket cells (PVBCs) evoked greater inhibition in CA1 PCs located in the deep compared to superficial layer of stratum pyramidale. In turn, analysis of reciprocal connectivity revealed more frequent excitatory inputs to PVBCs by superficial PCs, demonstrating bias in target selection by both the excitatory and inhibitory local connections in CA1. Additionally, PVBCs further segregated among deep PCs, preferentially innervating the amygdala-projecting PCs but receiving preferential excitation from the prefrontal cortex-projecting PCs, thus revealing distinct perisomatic inhibitory interactions between separate output channels. These results demonstrate the presence of heterogeneous PVBC-PC microcircuits, potentially contributing to the sparse and distributed structure of hippocampal network activity.

Quantitative assessment of CA1 local circuits: knowledge base for interneuron-pyramidal cell connectivity.

In this work, through a detailed literature review, data-mining, and extensive calculations, we provide a current, quantitative estimate of the cellular and synaptic constituents of the CA1 region of the rat hippocampus. Beyond estimating the cell numbers of GABAergic interneuron types, we calculate their convergence onto CA1 pyramidal cells and compare it with the known input synapses on CA1 pyramidal cells. The convergence calculation and comparison are also made for excitatory inputs to CA1 pyramidal cells. In addition, we provide a summary of the excitatory and inhibitory convergence onto interneurons. The quantitative knowledge base assembled and synthesized here forms the basis for data-driven, large-scale computational modeling efforts. Additionally, this work highlights specific instances where the available data are incomplete, which should inspire targeted experimental projects toward a more complete quantification of the CA1 neurons and their connectivity.

Toward a full-scale computational model of the rat dentate gyrus.

Recent advances in parallel computing, including the creation of the parallel version of the NEURON simulation environment, have allowed for a previously unattainable level of complexity and detail in neural network models. Previously, we published a functional NEURON model of the rat dentate gyrus with over 50,000 biophysically realistic, multicompartmental neurons, but network simulations could only utilize a single processor. By converting the model to take advantage of parallel NEURON, we are now able to utilize greater computational resources and are able to simulate the full-scale dentate gyrus, containing over a million neurons. This has eliminated the previous necessity for scaling adjustments and allowed for a more direct comparison to experimental techniques and results. The translation to parallel computing has provided a superlinear speedup of computation time and dramatically increased the overall computer memory available to the model. The incorporation of additional computational resources has allowed for more detail and elements to be included in the model, bringing the model closer to a more complete and accurate representation of the biological dentate gyrus. As an example of a major step toward an increasingly accurate representation of the biological dentate gyrus, we discuss the incorporation of realistic granule cell dendrites into the model. Our previous model contained simplified, two-dimensional dendritic morphologies that were identical for neurons of the same class. Using the software tools L-Neuron and L-Measure, we are able to introduce cell-to-cell variability by generating detailed, three-dimensional granule cell morphologies that are based on biological reconstructions. Through these and other improvements, we aim to construct a more complete full-scale model of the rat dentate gyrus, to provide a better tool to delineate the functional role of cell types within the dentate gyrus and their pathological changes observed in epilepsy.