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.

Contributions of dopaminergic and non-dopaminergic neurons to VTA-stimulation induced neurovascular responses in brain reward circuits.

Mapping the activity of the human mesolimbic dopamine system by BOLD-fMRI is a tempting approach to non-invasively study the action of the brain reward system during different experimental conditions. However, the contribution of dopamine release to the BOLD signal is disputed. To assign the actual contribution of dopaminergic and non-dopaminergic VTA neurons to the formation of BOLD responses in target regions of the mesolimbic system, we used two optogenetic approaches in rats. We either activated VTA dopaminergic neurons selectively, or dopaminergic and mainly glutamatergic projecting neurons together. We further used electrical stimulation to non-selectively activate neurons in the VTA. All three stimulation conditions effectively activated the mesolimbic dopaminergic system and triggered dopamine releases into the NAcc as measured by in vivo fast-scan cyclic voltammetry. Furthermore, both optogenetic stimulation paradigms led to indistinguishable self-stimulation behavior. In contrast to these similarities, however, the BOLD response pattern differed greatly between groups. In general, BOLD responses were weaker and sparser with increasing stimulation specificity for dopaminergic neurons. In addition, repetitive stimulation of the VTA caused a progressive decoupling of dopamine release and BOLD signal strength, and dopamine receptor antagonists were unable to block the BOLD signal elicited by VTA stimulation. To exclude that the sedation during fMRI is the cause of minimal mesolimbic BOLD in response to specific dopaminergic stimulation, we repeated our experiments using CBF SPECT in awake animals. Again, we found activations only for less-specific stimulation. Based on these results we conclude that canonical BOLD responses in the reward system represent mainly the activity of non-dopaminergic neurons. Thus, the minor effects of projecting dopaminergic neurons are concealed by non-dopaminergic activity, a finding which highlights the importance of a careful interpretation of reward-related human fMRI data.

Late effect of dopamine D1/5 receptor activation on stimulus-induced BOLD responses in the hippocampus and its target regions depends on the history of previous stimulations.

fMRI was used to study late effects of dopamine D1/5 receptor activation on hippocampal signal processing and signal propagation to several target regions. The dopamine D1/5 receptor agonists SKF83959 and SKF38393 were intraperitoneally applied without, immediately before or 7 days after electrical stimulation of the right perforant pathway with bursts of high-frequency pulses. Control animals received a 0.9% NaCl solution. One day after D1/5 receptor activation, the perforant pathway was stimulated and the induced BOLD responses in the right hippocampus and its target regions, left hippocampus (l-HC) and medial prefrontal cortex (mPFC), were measured. Depending on the temporal relation between dopamine receptor activation and the first perforant pathway stimulation the induced BOLD response pattern differed. When applied without concurrent perforant pathway stimulation, the agonists caused region-selective increases in the induced BOLD responses: the effect of SKF83959 was evident in the mPFC whereas that of SKF38393 was confined to the l-HC. When applied in conjunction with perforant pathway stimulation, either agonist caused increased BOLD responses in both regions. In contrast, when applied 7 days after perforant pathway stimulation, neither SKF83959 nor SKF38393 modified the BOLD responses in the mPFC or l-HC 1day later. These findings suggest that (i) activation of dopamine D1/5 receptors alone is sufficient to modify stimulus-induced BOLD responses in target regions of the right hippocampus 24h later, and (ii), the history of previous stimulations crucially affects the impact of dopamine receptor activation on stimulus-induced BOLD responses.

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

To determine the possibility to deconvolve measured BOLD responses to neuronal signals, the rat perforant pathway was electrically stimulated with 10 related stimulation protocols. All stimulation protocols were composed of low-frequency pulse sequences with superimposed high-frequency pulse bursts. Because high-frequency pulse bursts trigger only one synchronized spiking of granular cells, variations of the stimulation protocol were used: (a) to keep the spiking activity similar during the presentation of different numbers of pulses, (b) to apply identical numbers of pulses to induce different amounts of spiking activity, and (c) to concurrently vary the number of applied electrical pulses and resultant spiking activity. When complex pulse sequences enter the hippocampus, an unspecific default-like BOLD response is first generated, which relates neither to the number of incoming pulses nor to the induced spiking activity. Only during subsequent stimulations does the initial unspecific response adjust to a more adequate response, which in turn either strongly related to spiking activity when low-frequency pulses were applied or depended on the incoming activity when high-frequency pulse bursts were presented. Thus, only the development of BOLD responses during repetitive stimulations can predict the underlying neuronal activity and deconvolution analysis should not be performed during an initial stimulation period.

Sequential oogenesis is controlled by an oviduct factor in the locusts Locusta migratoria and Schistocerca gregaria: Overcoming the doctrine that patency in follicle cells is induced by juvenile hormone.

In insects that lay eggs in large clutches, yolk accumulation in each of the many ovarioles is restricted to the basal (terminal) oocyte, the one closest to the lateral oviduct. All succeeding (subterminal) oocytes remain small until the terminal oocytes finished their development and were ovulated into the oviduct. The major step regulating yolk uptake by terminal oocytes is the formation of gaps between cells of the follicle layer, a process termed patency. In the migratory as well as in the desert locust, patency is induced by a Patency Inducing Factor (PIF) produced by the lateral oviducts. PIF is secreted in all regions of the lateral oviducts and interacts with the basal follicle cells via the pedicel, a fine duct that connects an ovariole with the oviduct. By this mechanism, patency is triggered in the follicle cells of the terminal oocyte only, restricting yolk accumulation to the oocytes next to ovulation. In contrast to the previous hypothesis, juvenile hormone (JH) is not necessary to induce patency, rather JH amplifies the effect of PIF.

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.

Several human functional magnetic resonance imaging studies point to an activation of the mesolimbic dopamine system during reward, addiction and learning. We previously found activation of the mesolimbic system in response to continuous but not to discontinuous perforant pathway stimulation in an experimental model that we now used to investigate the role of dopamine release for the formation of functional magnetic resonance imaging responses. The two stimulation protocols elicited blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Inhibition of dopamine D1/5 receptors abolished the formation of functional magnetic resonance imaging responses in the medial prefrontal/anterior cingulate cortex during continuous but not during discontinuous pulse stimulations, i.e. only when the mesolimbic system was activated. Direct electrical or optogenetic stimulation of the ventral tegmental area caused strong dopamine release but only electrical stimulation triggered significant blood-oxygen level-dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. These functional magnetic resonance imaging responses were not affected by the D1/5 receptor antagonist SCH23390 but reduced by the N-methyl-D-aspartate receptor antagonist MK801. Therefore, glutamatergic ventral tegmental area neurons are already sufficient to trigger blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex and nucleus accumbens. Although dopamine release alone does not affect blood-oxygen-level dependent responses it can act as a switch, permitting the formation of blood-oxygen-level dependent responses.

The integrin inhibitor cilengitide affects meningioma cell motility and invasion.

PURPOSE: Meningiomas are frequent intracranial or spinal neoplasms, which recur frequently and can show aggressive clinical behaviour. We elucidated the impact of the integrin inhibitor cilengitide on migration, proliferation, and radiosensitization of meningioma cells. EXPERIMENTAL DESIGN: We analyzed integrin expression in tissue microarrays of human meningiomas and the antimeningioma properties of cilengitide in cell cultures, subcutaneous and intracranial nude mouse models by measuring tumor volumes and survival times. RESULTS: αvß5 was the predominantly expressed integrin heterodimer in meningiomas, whereas αvß3 was mainly detected in tumor blood vessels. Application of up to 100 µg/mL cilengitide resulted in only mildly reduced proliferation/survival of meningioma cell lines. Effects on cell survival could be enhanced by irradiation. One µg/mL cilengitide was sufficient to significantly inhibit meningioma cell migration and invasion in vitro. A daily dosage of 75 mg/kg did neither affect tumor volumes nor overall survival (P = 0.813, log-rank test), but suppressed brain invasion in a significant fraction of treated animals. A combination of 75 mg/kg cilengitide daily and irradiation (2 × 5 Gy) led to a 67% reduction of MRI-estimated tumor volumes in the intracranial model (P < 0.01), whereas the corresponding reduction reached by irradiation alone was only 55% (P < 0.05). CONCLUSIONS: These data show that a monotherapy with cilengitide is not likely to achieve major responses in rapidly growing malignant meningiomas, although brain invasion may be reduced because of the strong antimigratory properties of the drug. The combination with radiotherapy warrants further attention.

Variations in the temporal pattern of perforant pathway stimulation control the activity in the mesolimbic pathway.

Signal processing in the hippocampal formation and resultant signal propagation to cortical and subcortical structures during high frequency stimulation (i.e. 100 Hz) of the perforant pathway was studied in medetomidine anesthetized rats by functional magnetic resonance imaging (fMRI) and electrophysiological recordings. The perforant pathway was stimulated with bursts of 20 pulses, one burst per second, or with continuously applied pulses. The stimulation duration was adjusted to 8 s (short) or 30 s (long). In general, extending the stimulation duration only caused a local spreading of the fMRI response, but no changes in the magnitude of the fMRI response. This was in agreement with the electrophysiological responses, which also remained unchanged. In contrast, increasing the number of pulses in one stimulus train (i.e. changing from burst to continuous stimulation), caused both spreading and an increase in local fMRI responses that were accompanied by an altered neuronal response pattern. Continuous stimulation also triggered additional fMRI responses in the septum, nucleus accumbens, anterior cingulate cortex/medial prefrontal cortex, and ventral tegmental area/substantia nigra. The appearance of fMRI responses outside the hippocampal formation required at least 3 consecutive stimulation trains, characterized by region specific hemodynamic response functions. Thus, once triggered, continuous stimulation caused a sequential appearance in fMRI responses starting in the hippocampal formation, followed by signal changes in the ventral tegmental area/substantia nigra and anterior cingulate cortex/medial prefrontal cortex and eventually in the nucleus accumbens. These results indicate that high frequency stimulation of the hippocampal formation can activate the mesolimbic pathway, provided that repetitive stimulations are applied.