A comparison of how deep brain stimulation in two targets with anti-compulsive efficacy modulates brain activity using fMRI in awake rats.

Deep brain stimulation (DBS) is an established neuromodulatory intervention against otherwise treatment-refractory obsessive-compulsive disorder (OCD). Several DBS targets, all of which are part of brain networks connecting basal ganglia and prefrontal cortex, alleviate OCD symptoms. Stimulation of these targets is thought to unfold its therapeutic effect by modulation of network activity through internal capsule (IC) connections. Research into DBS-induced network changes and the nature of IC-related effects of DBS in OCD is needed to further improve DBS. Here, we studied the effects of DBS at the ventral medial striatum (VMS) and IC on blood-oxygen level dependent (BOLD) responses in awake rats using functional magnetic resonance imaging (fMRI). BOLD-signal intensity was measured in five regions of interest (ROIs): medial and orbital prefrontal cortex, nucleus accumbens (NAc), IC area, and mediodorsal thalamus. In previous rodent studies, stimulation at both target locations resulted in a reduction of OCD-like behavior and activation of prefrontal cortical areas. Therefore, we hypothesized that stimulation at both targets would result in partially overlapping BOLD responses. Both differential and overlapping activity between VMS and IC stimulation was found. Stimulating the caudal part of the IC resulted in activation around the electrode, while stimulating the rostral part of the IC resulted in increased cross-correlations between the IC area, orbitofrontal cortex, and NAc. Stimulation of the dorsal part of the VMS resulted in increased activity in the IC area, suggesting this area is activated during both VMS and IC stimulation. This activation is also indicative of VMS-DBS impacting corticofugal fibers running through the medial caudate into the anterior IC, and both VMS and IC DBS might act on these fibers to induce OCD-reducing effects. These results show that rodent fMRI with simultaneous electrode stimulation is a promising approach to study the neural mechanisms of DBS. Comparing the effects of DBS in different target areas has the potential to improve our understanding of the neuromodulatory changes that take place across various networks and connections in the brain. Performing this research in animal disease models will lead to translational insights in the mechanisms underlying DBS, and can aid improvement and optimization of DBS in patient populations.

A biophysical account of multiplication by a single neuron.

Nonlinear, multiplication-like operations carried out by individual nerve cells greatly enhance the computational power of a neural system1-3, but our understanding of their biophysical implementation is scant. Here we pursue this problem in the Drosophila melanogaster ON motion vision circuit4,5, in which we record the membrane potentials of direction-selective T4 neurons and of their columnar input elements6,7 in response to visual and pharmacological stimuli in vivo. Our electrophysiological measurements and conductance-based simulations provide evidence for a passive supralinear interaction between two distinct types of synapse on T4 dendrites. We show that this multiplication-like nonlinearity arises from the coincidence of cholinergic excitation and release from glutamatergic inhibition. The latter depends on the expression of the glutamate-gated chloride channel GluClα8,9 in T4 neurons, which sharpens the directional tuning of the cells and shapes the optomotor behaviour of the animals. Interacting pairs of shunting inhibitory and excitatory synapses have long been postulated as an analogue approximation of a multiplication, which is integral to theories of motion detection10,11, sound localization12 and sensorimotor control13.

Animal studies in clinical MRI scanners: A custom setup for combined fMRI and deep-brain stimulation in awake rats.

BACKGROUND: In humans, functional magnetic resonance imaging (fMRI) cannot be used to its full potential to study the effects of deep-brain stimulation (DBS) on the brain due to safety reasons. Application of DBS in small animals is an alternative, but was hampered by technical limitations thus far. NEW METHOD: We present a novel setup that extends the range of available applications by studying animals in a clinical scanner. We used a 3 T-MRI scanner with a custom-designed receiver coil and a restrainer to measure brain activity in awake rats. DBS electrodes made of silver were used to minimize electromagnetic artifacts. Before scanning, rats were habituated to the restrainer. RESULTS: Using our novel setup, we observed minor DBS-electrode artifacts, which did not interfere with brain-activity measurements significantly. Movement artifacts were also minimal and were not further reduced by restrainer habituation. Bilateral DBS in the dorsal part of the ventral striatum (dVS) resulted in detectable increases in brain activity around the electrodes tips. COMPARISON WITH EXISTING METHODS: This novel setup offers a low-cost alternative to dedicated small-animal scanners. Moreover, it can be implemented in widely available clinical 3 T scanners. Although spatial and temporal resolution was lower than what is achieved in anesthetized rats in high-field small-animal scanners, we obtained scans in awake animals, thus, testing the effects of bilateral DBS of the dVS in a more physiological state. CONCLUSIONS: With this new technical setup, the neurobiological mechanism of action of DBS can be explored in awake, restrained rats in a clinical 3 T-MRI scanner.

The Interaction of Munc18-1 Helix 11 and 12 with the Central Region of the VAMP2 SNARE Motif Is Essential for SNARE Templating and Synaptic Transmission.

Sec1/Munc18 proteins play a key role in initiating the assembly of N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, the molecular fusion machinery. Employing comparative structure modeling, site specific crosslinking by single amino acid substitutions with the photoactivatable unnatural amino acid p-Benzoyl-phenylalanine (Bpa) and reconstituted vesicle docking/fusion assays, we mapped the binding interface between Munc18-1 and the neuronal v-SNARE VAMP2 with single amino acid resolution. Our results show that helices 11 and 12 of domain 3a in Munc18-1 interact with the VAMP2 SNARE motif covering the region from layers -4 to +5. Residue Q301 in helix 11 plays a pivotal role in VAMP2 binding and template complex formation. A VAMP2 binding deficient mutant, Munc18-1 Q301D, does not stimulate lipid mixing in a reconstituted fusion assay. The neuronal SNARE-organizer Munc13-1, which also binds VAMP2, does not bypass the requirement for the Munc18-1·VAMP2 interaction. Importantly, Munc18-1 Q301D expression in Munc18-1 deficient neurons severely reduces synaptic transmission, demonstrating the physiological significance of the Munc18-1·VAMP2 interaction.