BOLD responses evoked by electrical stimulation of Locus Coeruleus in rats under anesthesia

We performed a whole-brain fMRI imaging in the rat under urethane anesthesia and studied BOLD responses induced by electrical stimulation of the brain stem noradrenergic nucleus Locus Coeruleus (LC). The rat was implanted with a MRI-compatible custom-made iridium electrode into LC under electrophysiological guidance. A 7T (300 MHz) magnet with a 30-cm horizontal bore (Bruker BioSpec 70/30, Ettlingen, Germany) equipped with a 20cm inner diameter gradient (Bruker BGA-20S Ettlingen, Germany) was used for MRI scanning. The experimental paradigm consisted of 6s baseline sampling, followed by 4s of unilateral LC stimulation and 10s of post-stimulus sampling. Biphasic square pulses (0.05-0.4mA) were delivered to LC at 20-100Hz either continuously for 4s or grouped in 100-500ms trains. These stimulation parameters were efficient in eliciting LC burst firing bilaterally. We also collected BOLD responses induced by peripheral sensory stimulation in the same animal and using the same experimental design (6/4/10s). For visual stimulation we used a luminance flicker presented to both eyes at 16Hz and delivered via fiber optic cables. A mild electrical stimulation (1-5mA) of a forepaw was used as somatosensory stimulation. The fMRI images were collected with spatial resolution of 0.4x0.4x1.0mm and temporal resolution of 1s. BOLD maps were generated by using GLM with standard (HRF-convolved boxcar functions) or neural regressors. We observed a remarkable dichotomy between BOLD responses of cortical and subcortical structures. Specifically, LC stimulation produced positive BOLD responses in the majority of structures belonging to metencephalon, mesencephalon and diencephalon, while negative BOLD responses in the entire neocortex. The robust neuronal activation in thalamic projections of LC was further confirmed by electrophysiological recordings. The cortical inhibition as a result of LC stimulation and associated NE release in cortical targets of LC has been reported in earlier studies. The peripheral sensory stimulation evoked both sensory-specific and non-specific activation/deactivation pattern. Strikingly, the regions of non-specific BOLD responses were common for both sensory modalities and largely overlapped with brain regions that showed responses to LC stimulation. We hypothesize that sensory stimulation activates modality-specific sensory pathways along with LC-NE system; and the LC co-activation produces the observed non-specific BOLD responses

BOLD responses evoked by electrical stimulation of Locus Coeruleus in rats under anesthesia

We performed a whole-brain fMRI imaging in the rat under urethane anesthesia and studied BOLD responses induced by electrical stimulation of the brain stem noradrenergic nucleus Locus Coeruleus (LC). The rat was first implanted with a MRI-compatible custom-made iridium electrode into LC under electrophysiological guidance. A 7T (300 MHz) magnet with a 30-cm horizontal bore (Bruker BioSpec 70/30, Ettlingen, Germany) equipped with a 20cm inner diameter gradient (Bruker BGA-20S Ettlingen, Germany) was used for MRI scanning. The experimental paradigm consisted of 6s base line sampling, followed by 4s of unilateral LC stimulation and 10s of post-stimulus sampling. Biphasic square pulses (0.05-0.4mA) were delivered to LC at 20-100Hz either continuously for 4s or grouped in 100-500ms trains. These stimulation parameters were efficient in eliciting LC burst firing bilaterally. We also collected BOLD responses induced by peripheral sensory stimulation in the same animal and using the same experimental design (6/4/10s). For visual stimulation we used a luminance flicker presented to both eyes at 16Hz and delivered via fiber optic cables. A mild electrical stimulation (1-5mA) of a forepaw was used as somatosensory stimulation. The fMRI images were collected with spatial resolution of 0.4x0.4x1.0mm and temporal resolution of 1s. BOLD maps were generated by using GLM with standard (HRF-convolved boxcar functions) or neural regressors. We observed a remarkable dichotomy between BOLD responses of cortical and subcortical structures. Specifically, LC stimulation produced positive BOLD responses in the majority of structures belonging to metencephalon, mesencephalon and diencephalon, while negative BOLD responses in the entire neocortex. The robust neuronal activation in thalamic projections of LC was further confirmed by electrophysiological recordings. The cortical inhibition as a result of LC stimulation and associated NE release in cortical targets of LC has been reported in earlier studies. The peripheral sensory stimulation evoked both sensory-specific and non-specific activation/deactivation pattern. Strikingly, the regions of non-specific BOLD responses were common for both sensory modalities and largely overlapped with brain regions that showed responses to LC stimulation. We hypothesize that sensory stimulation activates modality-specific sensory pathways along with LC-NE system; and the LC co-activation produces the observed non-specific BOLD responses

Rotationally resolved electronic spectroscopy of 5-methoxyindole

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Rotationally resolved electronic spectroscopy of 2,3-bridged indole derivatives: Tetrahydrocarbazole

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BOLD responses associated with hippocampal ripples in the rat brain

Hippocampal ripples, brief high-frequency oscillations, occur during behavioral states that are not associated with active sensory processing. The ripple event represents a simultaneous burst of a large neuronal population that is synchronized across the entire hippocampus. Reactivation of neuronal ensembles that were active during learning predominantly occurs during ripples. The number of ripples is increased after learning and this increase is predictive for memory recall. Ripple suppression is unfavorable for memory consolidation. Ripples have been suggested to provide a neurophysiological substrate for ‘off-line’ memory consolidation by facilitating synaptic plasticity within the learning-associated neuronal ensembles. The neuronal activity in other brain regions that is time-locked to hippocampal ripples may underlie a cross-regional information transfer. We exploited the methodology allowing simultaneous extracellular recording combined with fMRI. An anesthetized rat was fixed in the MRI scanner and MRI-compatible linear electrode array was placed with electrode contacts in cortex, hippocampus, and thalamus using a custom-made movable drive. Spontaneous whole-brain BOLD activity was acquired along with multi-site electrophysiological recording. The ripple events were detected and classified off-line using a custom software. The time series of BOLD responses were extracted for each voxel according to the event-triggered design, where the ripple onset was used as an event, and the statistical maps were generated indicating the voxels with positive and negative BOLD responses. The voxels were subsequently grouped according to the anatomical brain regions by co-registration of the functional images with the digital rat brain atlas. The positive BOLD response was detected within the direct proximity to the ripple recording site in the CA1 region of hippocampus. The most of the hippocampal volume was also co-activated. In addition, a number of cortical regions including sensory and associative cortices contained a substantial proportion of voxels showing positive BOLD responses. Several brain regions consistently showed negative BOLD responses. These included many of the thalamic nuclei, neuromodulatory nuclei of the midbrain and brain stem and cerebellum. The fMRI findings were further confirmed by electrophysiological recordings in multiple brain areas. Our results identify a brain network that possibly supports hippocampal-dependent memory consolidation. Besides, hippocampal ripples may cause a transient inhibition within competing functional networks to enable more efficient intra brain region communication

Studying large-scale brain networks: electrical stimulation and neural-event-triggered fMRI

The brain is "the" example of an adaptive, complex system. It is characterized by ultra-high structural complexity and massive connectivity, both of which change and evolve in response to experience. Information related to sensors and effectors is processed in both a parallel and a hierarchical fashion. The connectivity between different hierarchical levels is bidirectional, and its effectiveness is continuously controlled by specific associational and neuromodulatory centers. In the study of such systems one major problem is the adequate definition for an elementary operational unit (often called an "agent"), because any such module can be a complex system in its own right and may be recursively decomposed into other sets of units. A second difficulty arises from the synergistic organization of complex systems and of the brain in particular. Synergy here refers to the fact that the behavior of an integral, aggregate, whole system cannot be trivially reduced to, or predicted from, the components themselves. Localizing and comprehending the neural mechanisms underlying our cognitive capacities demands the combination of multimodal methodologies, i.e. it demands concurrent study of components and networks; one way of doing this, is to combine invasive methods which afford us direct access to the brain's electrical activity at the microcircuit level with global imaging technologies such as magnetic resonance imaging (MRI). In my talk, I'll discuss two such methodologies: Direct Electrical Stimulation and fMRI (DES-fMRI) and Neural-Event-Triggered fMRI (NET-fMRI). DES-fMRI can be used in hopes of gaining insight into the functional or effective connectivity underlying DES-induced behaviors. Yet, our first findings suggest that DES has an important limitation: It clearly demarcates all monosynaptic targets of a stimulated site, but it largely fails to reveal polysynaptic cortico-cortical connectivity. NET-fMRI, on the other hand, appears to offer great potential for mapping whole-brain activity that is associated with individual local events. In the second part of my talk, I'll describe the characteristic states of widespread cortical and subcortical networks that are associated with the occurrence of hippocampal sharp waves and ripples; the brief aperiodic episodes associated with memory consolidation

Hippocampal-cortical interaction during periods of subcortical silence

Hippocampal ripples, episodic high-frequency field-potential oscillations primarily occurring during sleep and calmness, have been described in mice, rats, rabbits, monkeys and humans, and so far they have been associated with retention of previously acquired awake experience. Although hippocampal ripples have been studied in detail using neurophysiological methods, the global effects of ripples on the entire brain remain elusive, primarily owing to a lack of methodologies permitting concurrent hippocampal recordings and whole-brain activity mapping. By combining electrophysiological recordings in hippocampus with ripple-triggered functional magnetic resonance imaging, here we show that most of the cerebral cortex is selectively activated during the ripples, whereas most diencephalic, midbrain and brainstem regions are strongly and consistently inhibited. Analysis of regional temporal response patterns indicates that thalamic activity suppression precedes the hippocampal population burst, which itself is temporally bounded by massive activations of association and primary cortical areas. These findings suggest that during off-line memory consolidation, synergistic thalamocortical activity may be orchestrating a privileged interaction state between hippocampus and cortex by silencing the output of subcortical centres involved in sensory processing or potentially mediating procedural learning. Such a mechanism would cause minimal interference, enabling consolidation of hippocampus-dependent memory