Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: From unspecific to adjusted, how the BOLD response in the rat hippocampus develops during consecutive stimulations

doi: 10.1177/0271678X16634715

Figure Lengend Snippet: Summary of the applied stimulation protocols. During all experiments, the perforant pathway was stimulated with 20 consecutive stimulation trains. The first stimulation train (indicated by red boxes) was applied 2 min after starting fMRI. Each stimulation train lasts for 8 s and was followed by 52 s rest (indicated by the gray boxes). During the first set of experiments, continuous 1, 5, 10, or 20 Hz pulses were applied during each stimulation train. During these stimulation frequencies, each applied pulse elicited one population spike; consequently, under these conditions, the input (i.e. applied pulses) and output activity (number of population spikes) vary in a similar way (Experiment 1). In a second set of experiments, high frequency pulses (5, 10, or 20) were superimposed on a 1 Hz stimulation protocol. Because only one population spike was generated to the first pulse of the burst during these conditions, whereas all subsequent pulses only generated fEPSPs, the number of population spikes was similar. Consequently, only the incoming activity varied, whereas the output activity remained similar (Experiment 2). During the third set of experiments, the perforant pathway was additionally stimulated with 5 Hz-4 pulses and 10 Hz-2 pulses; thus, there were four different experimental conditions in which 20 pulses were applied but different numbers of population spikes were generated (Experiment 3).

Article Snippet: To stimulate the hippocampal formation, a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques: Activity Assay, Generated

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: From unspecific to adjusted, how the BOLD response in the rat hippocampus develops during consecutive stimulations

doi: 10.1177/0271678X16634715

Figure Lengend Snippet: Summary of the measured BOLD responses in the right hippocampus during electrical stimulation of the right perforant pathway. Here, averaged maximal BOLD signal intensities during each BOLD response measured in experiment 1 (a), experiment 2 (b), and experiment 3 (c) are depicted. The averaged BOLD response during the first, fourth, and 18th–20th stimulation trains are summarized on the right. Asterisks indicate significantly increased BOLD response during train 4 when compared with train 1 (black: 20 Hz-1-pulse, dark blue: 1 Hz-50-pulse, turquoise: 10 Hz-2-pulse).

Article Snippet: To stimulate the hippocampal formation, a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques:

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: From unspecific to adjusted, how the BOLD response in the rat hippocampus develops during consecutive stimulations

doi: 10.1177/0271678X16634715

Figure Lengend Snippet: Summary of the electrophysiological responses in the right dentate gyrus during electrical stimulation of the right perforant pathway. Here, averaged population spike amplitudes during individual stimulus trains recorded in experiment 1 (a), experiment 2 (b), and experiment 3 (c) are depicted. The development of individual population spike amplitudes during the first, fourth, and 18th–20th stimulation trains are summarized on the right.

Article Snippet: To stimulate the hippocampal formation, a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques:

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: From unspecific to adjusted, how the BOLD response in the rat hippocampus develops during consecutive stimulations

doi: 10.1177/0271678X16634715

Figure Lengend Snippet: The relation between spiking activity (i.e. averaged population spike amplitude, see Figure 3) and the resultant BOLD response (see Figure 2) depends on the applied stimulation pattern. Strong correlations between these two factors were only found after an initial default-like BOLD response (i.e. induced by the first stimulation train, red dot) and followed by a short period of functional reconfiguration (train 2–4, pale dots). During stimulation with ≥ 10 high-frequency burst pulses, this correlation is nonexistent.

Article Snippet: To stimulate the hippocampal formation, a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques: Activity Assay, Functional Assay

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: From unspecific to adjusted, how the BOLD response in the rat hippocampus develops during consecutive stimulations

doi: 10.1177/0271678X16634715

Figure Lengend Snippet: Distribution of significantly activated voxels depends on the actual stimulation protocol. The applied stimulation protocol does not only determine the consistency of significant BOLD responses between early (i.e. train 5–11) and late (i.e. train 14–20) trains, but also the spatial distribution.

Article Snippet: To stimulate the hippocampal formation, a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques:

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: From unspecific to adjusted, how the BOLD response in the rat hippocampus develops during consecutive stimulations

doi: 10.1177/0271678X16634715

Figure Lengend Snippet: Application of an alternative stimulation protocol affects the development of BOLD responses to low frequency (5 Hz, green color) but not to high-frequency (1 Hz-20-pulse, blue color) stimulation. (a) Left panel: BOLD time series measured during alternate stimulations starting with a 5 Hz (protocol 1, top) or a 1 Hz-20-pulse (protocol 2, bottom) protocol. Middle panel: Summary of individual BOLD responses during stimulation and their respective decline over time (calculate between trains 5 and 20). Right panel: Averaged BOLD responses to 5 Hz and 1 Hz-20-pulse stimulation (between trains 5 and 20). (b) Left panel: BOLD time series measured during repetitive 5 Hz- and 1 Hz-20-pulse stimulations. Middle panel: Decline of BOLD responses during repetitive stimulations; top graph depicts all measuring points that correspond to protocol 1 and the lower graph depicts all measuring points that correspond to protocol 2. Right panel: average BOLD responses calculated from all responses between trains 5 and 20). (c) Comparison of BOLD responses observed during application of alternating or single stimulation protocols. An asterisk indicates a significant difference.

Article Snippet: To stimulate the hippocampal formation, a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques: Comparison

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: From unspecific to adjusted, how the BOLD response in the rat hippocampus develops during consecutive stimulations

doi: 10.1177/0271678X16634715

Figure Lengend Snippet: BOLD responses and the underlying alterations in neuronal activities.

Article Snippet: To stimulate the hippocampal formation, a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques: Activity Assay, Activation Assay

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat perforant pathway

doi: 10.1177/0271678X15615535

Figure Lengend Snippet: Stimulation protocols and activated pathways. (a) Electrical stimulation of the perforant pathway with continuous 100 Hz pulses for 8 s directly activates the hippocampal formation (HC, indicated by a dark shadow). The HC projects onto the septum, medial prefrontal cortex/anterior cingulate cortex (mPFC/ACC) and nucleus accumbens (NAcc) via glutamatergic fibers (indicated by solid red arrows). In addition, the HC activates the ventral tegmental area/substantia nigra (VTA/SN) region via an indirect pathway (indicated by a dashed red arrow). The VTA in turn projects onto the HC, septum, NAcc and mPFC/ACC via dopaminergic fibers (indicated by green arrows) and via non-dopaminergic fibers (indicated by pink arrows). Therefore, the NAcc, mPFC/ACC and septum receive glutamatergic and dopaminergic inputs. The stimulation protocol is depicted on top as a blue box (see Material and Methods). (b) Electrical stimulation of the perforant pathway with eight bursts of 20 pulses for 8 s with high intensity directly activates the HC (indicated by a dark shadow). Under this condition the HC projects onto the septum, mPFC/ACC and NAcc but not the VTA/SN region. Thus, the NAcc, mPFC/ACC and septum only receive glutamatergic inputs from the HC. (c) Stimulation of the VTA with laser light pulses only activates dopaminergic neurons (indicated by the green color) in this region. These neurons project to the HC, septum, NAcc and mPFC/ACC. The stimulation protocols are depicted on top as a blue box. (d) Electrical stimulation of the VTA directly activates dopaminergic (green) and non-dopaminergic (red) neurons in this region, which in turn project onto target regions of the mesolimbic system. The stimulation protocol is depicted on top as a blue box.

Article Snippet: To stimulate the HC formation a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques:

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat perforant pathway

doi: 10.1177/0271678X15615535

Figure Lengend Snippet: Optogenetic stimulation of dopaminergic neurons in the VTA. (a) An optical fiber was chronically implanted to deliver pulses of laser light to the VTA region. (b) The location of the VTA is indicated by the green color in the schematic brain atlas.18 (c) To confirm the right position the rats were trained to perform intracranial self-stimulation tasks. (d, e) Histological confirmation of opsin expression and fiber placement. WT: the CamKIIα-promoter led to expression of the green-fluorescent optogenetic construct around the injection site in the VTA. No expression of protein is evident in the dopaminergic cells of the Substantia nigra (SNc). Because of the placement of the fiber tip (*) close to the VTA, light spread is limited to this region and excitatory cells transduced further away from the tip are not excited by green light application. The smaller panels show a magnified view of the region below the fiber tip. A good correspondence between Tyrosine hydroxylase (TH) immunofluorescence (red) and opsin expression (green) is visible (circles), but not all dopaminergic cells have been transduced and some cells express opsin without also showing TH-immunofluorescence. TH-Cre: opsin expression (green) and Th-Immuno stain (red) in the same region as above but in transgenic rats expressing Cre-recombinase under the Th-promoter. Similarly to wild-type rats there is good co-localization of opsin expression and tyrosine-hydroxylase as expected from the Cre-loxP system. (f, g) BOLD response pattern caused by optogenetic activation of the VTA in wild-type rats (f) during 1 Hz (n = 10) or 25 Hz (n = 6) pulse stimulations and in TH-Cre rats (g) during 1 Hz (n = 2) or 25 Hz (n = 6) pulse stimulations. The location of the hippocampus is indicated by the dark ocher color. Regions with stimulus-related significantly increased BOLD signal intensities are marked in red and regions with stimulus-related significantly reduced BOLD signal intensities are marked in blue.

Article Snippet: To stimulate the HC formation a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques: Expressing, Construct, Injection, Immunofluorescence, Immunostaining, Transgenic Assay, Activation Assay

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat perforant pathway

doi: 10.1177/0271678X15615535

Figure Lengend Snippet: BOLD response pattern during electrical stimulation of the perforant pathway with continuous 100 Hz pulses for 8 s. (a) Spatial distribution of significantly activated voxels in one animal during repetitive stimulations of the perforant pathway. The analyzed regions of interest (ROIs) are indicated by red boxes.

Article Snippet: To stimulate the HC formation a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques:

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat perforant pathway

doi: 10.1177/0271678X15615535

Figure Lengend Snippet: Dopamine release into the nucleus accumbens as detected by in vivo fast-scan cyclic voltammetry. (a) Stimulation of the perforant pathway with continuous 100 Hz pulses for 8 s caused a detectable dopamine release into the NAcc (1.4 ± 0.2 µM). The dopamine release was transient and repeatable during consecutive stimulations (top part). The same stimulation protocol caused the generation of a widespread BOLD response in the rat brain including the NAcc region (lower part, arrow). (b) Laser light stimulation of dopaminergic neurons in the VTA caused a substantial transient dopamine release into the NAcc (4.6 ± 0.6 µM, top part). The dopamine release into the NAcc was not accompanied by significant changes in BOLD signal intensities in the NAcc area (lower part, arrow). Only in the colliculus superior region were significant stimulus-dependent changes in BOLD signal intensities observed. (c) Electrical stimulation of the VTA regions by 10 pulses at 100 Hz repetition rate caused transient dopamine release into the NAcc (3.5 ± 0.4 µM). The same stimulation protocol caused a complex significant BOLD response that included the NAcc region (lower part, arrow).

Article Snippet: To stimulate the HC formation a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques: In Vivo

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat perforant pathway

doi: 10.1177/0271678X15615535

Figure Lengend Snippet: BOLD response pattern during electrical stimulation of the perforant pathway with eight bursts of 20 pulses for 8 s. (a) Spatial distribution of significantly activated voxels in one animal during repetitive stimulations of the perforant pathway. (b) Three-dimensional visualization of significantly activated regions during repetitive stimulations of the perforant pathway with 10 trains of low-intensity pulses (250 µA) and during the subsequent 10 trains with high-intensity pulses (500 µA) during control conditions (n = 5) or in the presence of SKF83959 (n = 5), SCH23390 (n = 5) or MK801 (n = 5). (c) Summary of the BOLD time series in the right hippocampus, medial prefrontal cortex and nucleus accumbens during control condition (blue lines), in the presence of SCH23390 (red lines), MK801 (green lines) or SKF83959 (black lines). (d) The averaged responses to the last eight trains for the two conditions, i.e. during low- and high-intensity pulse intensities, are depicted at the right-hand side.

Article Snippet: To stimulate the HC formation a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques: Control

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat perforant pathway

doi: 10.1177/0271678X15615535

Figure Lengend Snippet: BOLD response pattern during electrical stimulation of the ventral tegmental area with continuous 1 Hz pulses or eight bursts of 10 pulses for 8 s. (a) Spatial distribution of significantly activated voxels during electrical stimulation of the VTA in one animal. Red boxes mark the regions of interest. (b) Three-dimensional visualization of significantly activated regions during repetitive electrical stimulations of the VTA with continuous 1 Hz pulses or eight bursts of 10 pulses. (c) The corresponding BOLD time series in the mPFC/ACC under control condition revealed that the generation of similar BOLD responses requires more than a continuous 1 Hz-pulse stimulation. (d) Comparison of the BOLD time series in the three regions under control condition (blue lines, n = 7), in the presence of SCH23390 (red lines, n = 7) and MK801 (green lines, n = 7). To visualize the effects of the two antagonists the averaged BOLD responses (train 1–10) are depicted in the right-hand panel.

Article Snippet: To stimulate the HC formation a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques: Control, Comparison

Journal: Journal of Cerebral Blood Flow & Metabolism

Article Title: The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat perforant pathway

doi: 10.1177/0271678X15615535

Figure Lengend Snippet: Summary of the observed BOLD responses during the applied stimulation protocols. The hemodynamic response functions (HRF), characterizing the BOLD response, are compared. (a) Electrical stimulation of the perforant pathway with continuous 100 Hz pulses for 8 s triggered BOLD responses in various regions of the rat brain. During this stimulation condition the maximal BOLD response in the NAcc (orange line) exceeded the maximal BOLD response in the mPFC/ACC (blue line). (b) Electrical stimulation of the perforant pathway with bursts of high-intensity pulses also triggered BOLD responses in various regions of the brain. Under this stimulation condition the BOLD response in the mPFC/ACC (blue line) exceeded the response in the NAcc (orange line). (c) Electrical stimulation of the VTA also triggered BOLD responses in various regions. Again the BOLD response in the mPFC/ACC (blue line) exceeded the response in the NAcc (orange line). (d) Comparison of the HRFs in the mPFC/ACC during all stimulation conditions. Whereas the initial slope of the HRF was similar during electrical VTA (dotted line) and high-intensity burst pulse stimulations of perforant pathway (dashed line), the initial slope was delayed during low-intensity continuously pulse stimulation (solid line). For comparison, the effects of SCH23390 (red solid line) and MK801 (green solid line) on the BOLD response during continuous 100 Hz pulse stimulations are included. (e) The initial slope of the HRF in the NAcc was similar during all stimulation conditions. The presence of MK801 almost abolished the formation of a BOLD response in the NAcc during continuous 100 Hz pulse stimulation. (f) The initial slope of the HRF observed in the VTA/SN region during electrical stimulation of the VTA (dotted line) and during electrical stimulation of perforant pathway with continuous 100 Hz pulses was identical. Again, the presence of MK801 inhibited the BOLD response in the VTA/SN region.

Article Snippet: To stimulate the HC formation a bipolar stimulation electrode (114 μm in diameter, Teflon-coated tungsten wire, A-M Systems) was placed into the perforant pathway (AP: −6.9 mm; ML + 4.1 mm from Bregma; DV 2.3–3.0 mm from dural surface) of the right hemisphere, according to the atlas of Paxinos and Watson.

Techniques: Comparison