Interferon-γ acutely augments inhibition of neocortical layer 5 pyramidal neurons

BACKGROUND: Interferon-γ (IFN-γ, a type II IFN) is present in the central nervous system (CNS) under various conditions. Evidence is emerging that, in addition to its immunological role, IFN-γ modulates neuronal morphology, function, and development in several brain regions. Previously, we have shown that raising levels of IFN-β (a type I IFN) lead to increased neuronal excitability of neocortical layer 5 pyramidal neurons. Because of shared non-canonical signaling pathways of both cytokines, we hypothesized a similar neocortical role of acutely applied IFN-γ. METHODS: We used semi-quantitative RT-PCR, immunoblotting, and immunohistochemistry to analyze neuronal expression of IFN-γ receptors and performed whole-cell patch-clamp recordings in layer 5 pyramidal neurons to investigate sub- and suprathreshold excitability, properties of hyperpolarization-activated cyclic nucleotide-gated current (Ih), and inhibitory neurotransmission under the influence of acutely applied IFN-γ. RESULTS: We show that IFN-γ receptors are present in the membrane of rat's neocortical layer 5 pyramidal neurons. As expected from this and the putative overlap in IFN type I and II alternative signaling pathways, IFN-γ diminished Ih, mirroring the effect of type I IFNs, suggesting a likewise activation of protein kinase C (PKC). In contrast, IFN-γ did neither alter subthreshold nor suprathreshold neuronal excitability, pointing to augmented inhibitory transmission by IFN-γ. Indeed, IFN-γ increased electrically evoked inhibitory postsynaptic currents (IPSCs) on neocortical layer 5 pyramidal neurons. Furthermore, amplitudes of spontaneous IPSCs and miniature IPSCs were elevated by IFN-γ, whereas their frequency remained unchanged. CONCLUSIONS: The expression of IFN-γ receptors on layer 5 neocortical pyramidal neurons together with the acute augmentation of inhibition in the neocortex by direct application of IFN-γ highlights an additional interaction between the CNS and immune system. Our results strengthen our understanding of the role of IFN-γ in neocortical neurotransmission and emphasize its impact beyond its immunological properties, particularly in the pathogenesis of neuropsychiatric disorders

Temporally Graded Activation of Neocortical Regions in Response to Memories of Different Ages

The temporally graded memory impairment seen in many neurobehavioral disorders implies different neuroanatomical pathways and/or cognitive mechanisms involved in storage and retrieval of memories of different ages. A dynamic interaction between medial-temporal and neocortical brain regions has been proposed to account for memory\u27s greater permanence with time. Despite considerable debate concerning its time-dependent role in memory retrieval, medial-temporal lobe activity has been well studied. However, the relative participation of neocortical regions in recent and remote memory retrieval has received much less attention. Using functional magnetic resonance imaging, we demonstrate robust, temporally graded signal differences in posterior cingulate, right middle frontal, right fusiform, and left middle temporal regions in healthy older adults during famous name identification from two disparate time epochs. Importantly, no neocortical regions demonstrated greater response to older than to recent stimuli. Our results suggest a possible role of these neocortical regions in temporally dating items in memory and in establishing and maintaining memory traces throughout the lifespan. Theoretical implications of these findings for the two dominant models of remote memory functioning (Consolidation Theory and Multiple Trace Theory) are discussed

Self-wiring in neural nets of point-like cortical neurons fails to reproduce cytoarchitectural differences

We propose a model for description of activity-dependent evolution and self-wiring between binary neurons. Specifically, this model can be used for investigation of growth of neuronal connectivity in the developing neocortex. By using computational simulations with appropriate training pattern sequences, we show that long-term memory can be encoded in neuronal connectivity and that the external stimulations form part of the functioning neocortical circuit. It is proposed that such binary neuron representations of point-like cortical neurons fail to reproduce cytoarchitectural differences of the neocortical organization, which has implications for inadequacies of compartmental models.Comment: 13 pages, 5 figure

Statistical mechanics of neocortical interactions: EEG eigenfunctions of short-term memory

This paper focuses on how bottom-up neocortical models can be developed into eigenfunction expansions of probability distributions appropriate to describe short-term memory in the context of scalp EEG. The mathematics of eigenfunctions are similar to the top-down eigenfunctions developed by Nunez, albeit they have different physical manifestations. The bottom-up eigenfunctions are at the local mesocolumnar scale, whereas the top-down eigenfunctions are at the global regional scale. However, as described in several joint papers, our approaches have regions of substantial overlap, and future studies may expand top-down eigenfunctions into the bottom-up eigenfunctions, yielding a model of scalp EEG that is ultimately expressed in terms of columnar states of neocortical processing of attention and short-term memory.Comment: 5 PostScript page

Statistical mechanics of neocortical interactions: High resolution path-integral calculation of short-term memory

We present high-resolution path-integral calculations of a previously developed model of short-term memory in neocortex. These calculations, made possible with supercomputer resources, supplant similar calculations made in L. Ingber, Phys. Rev. E 49, 4652 (1994), and support coarser estimates made in L. Ingber, Phys. Rev. A 29, 3346 (1984). We also present a current experimental context for the relevance of these calculations using the approach of statistical mechanics of neocortical interactions, especially in the context of electroencephalographic data.Comment: 35 PostScript pages, including 14 figure

Influence of barium on rectification in rat neocortical neurons

The effect of low concentrations of barium on the membrane properties of rat neocortical neurons was studied in vitro. Potassium currents were examined using single-electrode current- and voltage-clamp techniques. Neurons responded to bath application of barium (10–100 μM) with a membrane depolarization associated with an increase in input resistance. Under voltage clamp conditions, an inward shift in holding current was observed. The effects of barium were rapidly reversible upon washing and persisted in the presence of TTX. The equilibrium potential for the barium-induced inward current was near −110 mV, suggesting that barium inhibited a tonically active potassium conductance. Measurements of current voltage relationships indicated an inward rectification of this conductance between −50 and −130 mV. These results provide strong evidence that barium blocks a persistent potassium ‘leak’ current in neocortical neurons that contributes to the resting potential of these cells

EPSPs in rat neocortical neurons in vitro. I. Electrophysiological evidence for two distinct EPSPs

1. To investigate excitatory postsynaptic potentials (EPSPs), intracellular recordings were performed in layer II/III neurons of the rat medial frontal cortex. The average resting membrane potential of the neurons was more than -75 mV and their average input resistance was greater than 20 M omega. The amplitudes of the action potentials evoked by injection of depolarizing current pulses were greater than 100 mV. The electrophysiological properties of the neurons recorded were similar to those of regular-spiking pyramidal cells. 2. Current-voltage relationships, determined by injecting inward and outward current pulses, displayed considerable inward rectification in both the depolarizing and hyperpolarizing directions. The steady-state input resistance increased with depolarization and decreased with hyperpolarization, concomitant with increases and decreases, respectively, in the membrane time constant. 3. Postsynaptic potentials were evoked by electrical stimulation via a bipolar electrode positioned in layer IV of the neocortex. Stimulus-response relationships, determined by gradually increasing the stimulus intensity, were consistent among the population of neurons examined. A short-latency EPSP [early EPSP (eEPSP)] was the response with the lowest threshold. Amplitudes of the eEPSP ranged from 4 to 8 mV. Following a hyperpolarization of the membrane potential, the amplitude of the eEPSP decreased. Upon depolarization, a slight increase in amplitude and duration was observed, accompanied by a significant increase in time to peak. 4. The membrane current underlying the eEPSP (eEPSC) was measured using the single-electrode voltage-clamp method. The amplitude of the eEPSC was apparently independent of the membrane potential in 8 of 12 neurons tested. In the other 4 neurons, the amplitude of the eEPSC increased with hyperpolarization and decreased with depolarization. 5. Higher stimulus intensities evoked, in addition to the eEPSP, a delayed EPSP [late EPSP (lEPSP)] in greater than 90% of the neurons tested. The amplitude of the lEPSP ranged from 12 to 20 mV, and the latency varied between 20 and 60 ms. The amplitude of the lEPSP varied with membrane potential, decreasing with depolarization and increasing following hyperpolarization. The membrane current underlying the lEPSP (lEPSC) displayed a similar voltage dependence. 6. At stimulus intensities that led to the activation of inhibitory postsynaptic potentials (IPSPs), the lEPSP was no longer observed

Quantum calcium-ion interactions with EEG

Previous papers have developed a statistical mechanics of neocortical interactions (SMNI) fit to short-term memory and EEG data. Adaptive Simulated Annealing (ASA) has been developed to perform fits to such nonlinear stochastic systems. An N-dimensional path-integral algorithm for quantum systems, qPATHINT, has been developed from classical PATHINT. Both fold short-time propagators (distributions or wave functions) over long times. Previous papers applied qPATHINT to two systems, in neocortical interactions and financial options. \textbf{Objective}: In this paper the quantum path-integral for Calcium ions is used to derive a closed-form analytic solution at arbitrary time that is used to calculate interactions with classical-physics SMNI interactions among scales. Using fits of this SMNI model to EEG data, including these effects, will help determine if this is a reasonable approach. \textbf{Method}: Methods of mathematical-physics for optimization and for path integrals in classical and quantum spaces are used for this project. Studies using supercomputer resources tested various dimensions for their scaling limits. In this paper the quantum path-integral is used to derive a closed-form analytic solution at arbitrary time that is used to calculate interactions with classical-physics SMNI interactions among scales. \textbf{Results}: The mathematical-physics and computer parts of the study are successful, in that there is modest improvement of cost/objective functions used to fit EEG data using these models. \textbf{Conclusion}: This project points to directions for more detailed calculations using more EEG data and qPATHINT at each time slice to propagate quantum calcium waves, synchronized with PATHINT propagation of classical SMNI.Comment: published in Sc

Characteristics of long-duration inhibitory postsynaptic potentials in rat neocortical neurons in vitro

1. The characteristics of long-duration inhibitory postsynaptic potentials (l-IPSPs) which are evoked in rat frontal neocortical neurons by local electrical stimulation were investigated with intracellular recordings from anin vitro slice preparation. 2. Stimulation with suprathreshold intensities evoked l-IPSPs with typical durations of 600–900 msec at resting membrane potential. Conductance increases of 15–60% were measured at the peak amplitude of l-IPSPs (150–250 msec poststimulus). 3. The duration of the conductance increases during l-IPSPs displayed a significant voltage dependence, decreasing as the membrance potential was depolarized and increasing with hyperpolarization. 4. The reversal potential of l-IPSPs is significantly altered by reductions in the extracellular potassium concentration. Therefore it is concluded that l-IPSPs in rat neocortical neurons are generated by the activation of a potassium conductance. 5. l-IPSPs exhibit stimulation fatigue. Stimulation with a frequency of 1 Hz produces a complete fatigue of the conductance increases during l-IPSPs after approximately 20 consecutive stimuli. Recovery from this fatigue requires minutes. 6. l-IPSPs are not blocked by bicuculline but are blocked by baclofen