Electrical Stimulation of the Lateral Entorhinal Cortex Causes a Frequency-Specific BOLD Response Pattern in the Rat Brain

Although deep brain stimulation of the entorhinal cortex has recently shown promise in the treatment of early forms of cognitive decline, the underlying neurophysiological processes remain elusive. Therefore, the lateral entorhinal cortex (LEC) was stimulated with trains of continuous 5 Hz and 20 Hz pulses or with bursts of 100 Hz pulses to visualize activated neuronal networks, i.e., neuronal responses in the dentate gyrus and BOLD responses in the entire brain were simultaneously recorded. Electrical stimulation of the LEC caused a wide spread pattern of BOLD responses. Dependent on the stimulation frequency, BOLD responses were only triggered in the amygdala, infralimbic, prelimbic, and dorsal peduncular cortex (5 Hz), or in the nucleus accumbens, piriform cortex, dorsal medial prefrontal cortex, hippocampus (20 Hz), and contralateral entorhinal cortex (100 Hz). In general, LEC stimulation caused stronger BOLD responses in frontal cortex regions than in the hippocampus. Identical stimulation of the perforant pathway, a fiber bundle projecting from the entorhinal cortex to the dentate gyrus, hippocampus proper, and subiculum, mainly elicited significant BOLD responses in the hippocampus but rarely in frontal cortex regions. Consequently, BOLD responses in frontal cortex regions are mediated by direct projections from the LEC rather than via signal propagation through the hippocampus. Thus, the beneficial effects of deep brain stimulation of the entorhinal cortex on cognitive skills might depend more on an altered prefrontal cortex than hippocampal function

Evolution of shear zones in granular materials

The evolution of wide shear zones (or shear bands) was investigated experimentally and numerically for quasistatic dry granular flows in split bottom shear cells. We compare the behavior of materials consisting of beads, irregular grains (e.g. sand) and elongated particles. Shearing an initially random sample, the zone width was found to significantly decrease in the first stage of the process. The characteristic shear strain associated with this decrease is about unity and it is systematically increasing with shape anisotropy, i.e. when the grain shape changes from spherical to irregular (e.g. sand) and becomes elongated (pegs). The strongly decreasing tendency of the zone width is followed by a slight increase which is more pronounced for rod like particles than for grains with smaller shape anisotropy (beads or irregular particles). The evolution of the zone width is connected to shear induced density change and for nonspherical particles it also involves grain reorientation effects. The final zone width is significantly smaller for irregular grains than for spherical beads.Comment: 11 pages, 12 figures, submitted to Phys. Rev.

Reflection and Exclusion of Shear Zones in Inhomogeneous Granular Materials

Shear localization in granular materials is studied experimentally and numerically. The system consists of two material layers with different effective frictions. The presence of the material interface leads to a special type of "total internal reflection" of the shear zone. In a wide range of configurations the reflection is characterized by a fixed angle which is analogous to the critical angle of refraction in optics. The zone leaves and reenters the high friction region at this critical angle and in between it stays near the interface in the low friction region. The formalism describing the geometry of the shear zones and that of refracted and reflected light beams is very similar. For the internal visualization of shear localization two independent experimental techniques were used (i) excavation and (ii) Magnetic Resonance Imaging.Comment: 8 pages, 9 figures; Final version published in Soft Matter (2011

Toxoplasma gondii Actively Inhibits Neuronal Function in Chronically Infected Mice

Upon infection with the obligate intracellular parasite Toxoplasma gondii, fast replicating tachyzoites infect a broad spectrum of host cells including neurons. Under the pressure of the immune response, tachyzoites convert into slow-replicating bradyzoites, which persist as cysts in neurons. Currently, it is unclear whether T. gondii alters the functional activity of neurons, which may contribute to altered behaviour of T. gondii–infected mice and men. In the present study we demonstrate that upon oral infection with T. gondii cysts, chronically infected BALB/c mice lost over time their natural fear against cat urine which was paralleled by the persistence of the parasite in brain regions affecting behaviour and odor perception. Detailed immunohistochemistry showed that in infected neurons not only parasitic cysts but also the host cell cytoplasm and some axons stained positive for Toxoplasma antigen suggesting that parasitic proteins might directly interfere with neuronal function. In fact, in vitro live cell calcium (Ca2+) imaging studies revealed that tachyzoites actively manipulated Ca2+ signalling upon glutamate stimulation leading either to hyper- or hypo-responsive neurons. Experiments with the endoplasmatic reticulum Ca2+ uptake inhibitor thapsigargin indicate that tachyzoites deplete Ca2+ stores in the endoplasmatic reticulum. Furthermore in vivo studies revealed that the activity-dependent uptake of the potassium analogue thallium was reduced in cyst harbouring neurons indicating their functional impairment. The percentage of non-functional neurons increased over time In conclusion, both bradyzoites and tachyzoites functionally silence infected neurons, which may significantly contribute to the altered behaviour of the host

Frequency-dependent electrical stimulation of fimbria-fornix preferentially affects the mesolimbic dopamine system or prefrontal cortex

BACKGROUND: The fimbria/fornix fiber system is an essential part of the hippocampal-VTA loop, and therefore activities that are propagated through this fiber system control the activity of the mesolimbic dopamine system. OBJECTIVES/HYPOTHESIS: We hypothesized that stimulation of the fimbria/fornix with an increasing number of electrical pulses would cause increasing activity of the mesolimbic dopamine system, which coincides with concurrent changes in neuronal activities in target regions of the mesolimbic dopaminergic system. METHODS:Right fimbria/fornix fibers were electrically stimulated with different pulse protocols. Stimulus-induced changes in neuronal activities were visualized with BOLD-fMRI, whereas stimulus-induced release of dopamine, as measured for the activity of the mesolimbic dopamine system, was determined in the nucleus accumbens with in vivo fast-scan cyclic voltammetry. RESULTS: Dependent on the protocol, electrical fimbria/fornix stimulation caused BOLD responses in various targets of the mesolimbic dopamine system. Stimulation in the low theta frequency range (5 Hz) triggered significant BOLD responses mainly in the hippocampal formation, infralimbic cortex, and septum. Stimulation in the beta frequency range (20 Hz) caused additional activation in the medial prefrontal cortex (mPFC), nucleus accumbens, striatum, and VTA. Stimulation in the high-gamma frequency range (100 Hz) caused further activation in the hippocampus proper and mPFC. The strong activation in the mPFC during 100 Hz stimulations depended not only on the number of pulses but also on the frequency. Thus, short bursts of 5 or 20 high-frequency pulses caused stronger activation in the mPFC than continuous 5 or 20 Hz pulses. In contrast, high-frequency burst fimbria/fornix stimulation did not further activate the mesolimbic dopamine system when compared to continuous 5 or 20 Hz pulse stimulation. CONCLUSIONS: There exists a frequency-dependent dissociation between BOLD responses and activation of the dopaminergic system. Low frequencies were more efficient to activate the mesolimbic dopamine system, whereas high frequencies were more efficient to trigger BOLD responses in target regions of the mesolimbic dopamine system, particularly the mPFC

Hippocampal CA3 activation alleviates fMRI-BOLD responses in the rat prefrontal cortex induced by electrical VTA stimulation

Functional magnetic resonance imaging (fMRI) was used to identify brain- wide networks that are activated by electrical stimulation of either the ventral tegmental area (VTA) or hippocampal CA3 region. Stimulation of either one of these regions caused significant BOLD responses in common structures, such as the septum and left and right hippocampus, but also in unique structures, such as the medial prefrontal cortex region/anterior cingulum region (mPFC/ACC) and striatum, which were only activated during VTA stimulation. Concurrent stimulations of the two structures resulted in no additive BOLD responses but significantly reduced BOLD responses in the mPFC/ACC when compared with sole VTA stimulation. This reduction is caused by costimulation of the hippocampal CA3 region, which was itself not sufficient to modify BOLD signal intensities in the mPFC/ACC. Under this experimental condition, functional connectivity between VTA and mPFC/ACC in terms of neurophysiological interactions was causative, driven by direct electrical stimulation of VTA projecting neurons, the resulting functional connectivity in terms of correlated BOLD time series becoming masked as soon as hippocampal projections concurrently coactivated mPFC neurons. This result warns against misinterpretation of the absence of functional connectivity in fMRI data sets, because strong existing neurophysiological interactions can be obscured by unrelated network activities

The cholinergic system modulates negative BOLD responses in the prefrontal cortex once electrical perforant pathway stimulation triggers neuronal afterdischarges in the hippocampus

Repeated high-frequency pulse-burst stimulations of the rat perforant pathway elicited positive BOLD responses in the right hippocampus, septum and prefrontal cortex. However, when the first stimulation period also triggered neuronal afterdischarges in the hippocampus, then a delayed negative BOLD response in the prefrontal cortex was generated. While neuronal activity and cerebral blood volume (CBV) increased in the hippocampus during the period of hippocampal neuronal afterdischarges (h-nAD), CBV decreased in the prefrontal cortex, although neuronal activity did not decrease. Only after termination of h-nAD did CBV in the prefrontal cortex increase again. Thus, h-nAD triggered neuronal activity in the prefrontal cortex that counteracted the usual neuronal activity-related functional hyperemia. This process was significantly enhanced by pilocarpine, a mACh receptor agonist, and completely blocked when pilocarpine was co-administered with scopolamine, a mACh receptor antagonist. Scopolamine did not prevent the formation of the negative BOLD response, thus mACh receptors modulate the strength of the negative BOLD response

Electrical Stimulation of the Lateral Entorhinal Cortex Causes a Frequency-Specific BOLD Response Pattern in the Rat Brain

Although deep brain stimulation of the entorhinal cortex has recently shown promise in the treatment of early forms of cognitive decline, the underlying neurophysiological processes remain elusive. Therefore, the lateral entorhinal cortex (LEC) was stimulated with trains of continuous 5 Hz and 20 Hz pulses or with bursts of 100 Hz pulses to visualize activated neuronal networks, i.e., neuronal responses in the dentate gyrus and BOLD responses in the entire brain were simultaneously recorded. Electrical stimulation of the LEC caused a wide spread pattern of BOLD responses. Dependent on the stimulation frequency, BOLD responses were only triggered in the amygdala, infralimbic, prelimbic, and dorsal peduncular cortex (5 Hz), or in the nucleus accumbens, piriform cortex, dorsal medial prefrontal cortex, hippocampus (20 Hz), and contralateral entorhinal cortex (100 Hz). In general, LEC stimulation caused stronger BOLD responses in frontal cortex regions than in the hippocampus. Identical stimulation of the perforant pathway, a fiber bundle projecting from the entorhinal cortex to the dentate gyrus, hippocampus proper, and subiculum, mainly elicited significant BOLD responses in the hippocampus but rarely in frontal cortex regions. Consequently, BOLD responses in frontal cortex regions are mediated by direct projections from the LEC rather than via signal propagation through the hippocampus. Thus, the beneficial effects of deep brain stimulation of the entorhinal cortex on cognitive skills might depend more on an altered prefrontal cortex than hippocampal function

Summary of applied stimulation protocols and VOI analysis.

<p>(A) During one experiment, three consecutive stimulation blocks were applied, and every stimulation block consisted of identical stimulation trains. One stimulation train lasted 8 s followed by 52 s rest; thus, one train every minute. Colors indicate the forms of stimulation. blue: left CA3, red: VTA, and green: CA3 and VTA stimulation. (B) Summary of applied pulses per stimulation train. The left CA3 was stimulated with continuous 2-Hz pulses (indicated by black lines). VTA was stimulated with eight bursts of 10 pulses (inter-pulse interval 10 ms), one burst/s. For costimulation, the onset of continuous 2-Hz pulse CA3 stimulation was delayed by 200 ms to prevent stimulation artifacts from the VTA stimulation from interfering with the recording of field potentials in the CA1 region during low-frequency CA3 stimulations. (C) Location of stimulation and recording electrodes (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172926#sec002" target="_blank">Material and Method</a> section). (D) Location of analyzed VOIs (NAcc–nucleus accumbens, mPFC/ACC–medial prefrontal cortex/anterior cingulum). For each animal, BOLD time series of all voxels located in one VOI were averaged and depicted as BOLD time series of the appropriate VOI. For group analysis, VOI BOLD time series from all individual animals were averaged.</p