A Novel Neural Substrate for the Transformation of Olfactory Inputs into Motor Output

Anatomical and physiological experiments in the lamprey reveal the neural circuit involved in transforming olfactory inputs into motor outputs, which was previously unknown in a vertebrate

GABAergic modulation of olfactomotor transmission in lampreys.

Odor-guided behaviors, including homing, predator avoidance, or food and mate searching, are ubiquitous in animals. It is only recently that the neural substrate underlying olfactomotor behaviors in vertebrates was uncovered in lampreys. It consists of a neural pathway extending from the medial part of the olfactory bulb (medOB) to locomotor control centers in the brainstem via a single relay in the caudal diencephalon. This hardwired olfactomotor pathway is present throughout life and may be responsible for the olfactory-induced motor behaviors seen at all life stages. We investigated modulatory mechanisms acting on this pathway by conducting anatomical (tract tracing and immunohistochemistry) and physiological (intracellular recordings and calcium imaging) experiments on lamprey brain preparations. We show that the GABAergic circuitry of the olfactory bulb (OB) acts as a gatekeeper of this hardwired sensorimotor pathway. We also demonstrate the presence of a novel olfactomotor pathway that originates in the non-medOB and consists of a projection to the lateral pallium (LPal) that, in turn, projects to the caudal diencephalon and to the mesencephalic locomotor region (MLR). Our results indicate that olfactory inputs can induce behavioral responses by activating brain locomotor centers via two distinct pathways that are strongly modulated by GABA in the OB. The existence of segregated olfactory subsystems in lampreys suggests that the organization of the olfactory system in functional clusters may be a common ancestral trait of vertebrates

Glutamate injection into the OB induces fictive locomotion.

<p>(A) Top trace: Intracellular recording of a RS cell. Note the large excitation induced by the injection of 3 mM glutamate in the ipsilateral OB. Bottom traces: Ventral root (VR) discharges on both sides. (B) Detail from the boxed area in (B) shows fictive locomotion characterized by alternating ipsilateral and contralateral ventral root activity (iVR and cVR, respectively). Note that the RS cell shows rhythmic oscillations in tune with the fictive locomotor pattern.</p

Olfactory-locomotor information transits through the medial region of the OB.

<p>(A–D) Responses in a single ipsilateral RS neuron to 30 µA stimulation of the ON and OB. The schematic (inset) indicates the location of stimulating electrodes. Note that a synaptic response was elicited only following stimulation of the ON or the medial part of the OB. (E) Mean amplitude of 4 RS cells responses to 30 µA ON stimulation before (grey bar) and after local injection of AP5 and CNQX mixture in the central-medial OB (red bar) and lateral OB (green bar). * <i>p</i><0.05.</p

The medial region of the OB projects to the PT.

<p>(A) Schematic dorsal view of the forebrain summarizing the efferent OB projections in the lamprey. Projections from OB regions other than the medial region are shown in green. (B) Anterograde labeling from the medial OB (red) shows fibers terminating in the PT (see picture to the right). (C, D) Retrograde labeling from the PT shows neuronal cell bodies in only one medial glomerulus in the OB (see picture to the right). (E, F) Retrograde labeling from the lateral pallium shows neurons associated with almost all glomeruli, except the medial. White scale bars in pictures represent 100 µm.</p

Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial

Background: Current standard of care for trigeminal neuralgia is treatment with the sodium channel blockers carbamazepine and oxcarbazepine, which although effective are associated with poor tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent sodium-channel blocker, can be administered at therapeutic doses without titration, and has shown good tolerability in healthy individuals in phase 1 studies. We therefore assessed the safety and efficacy of BIIB074 in patients with trigeminal neuralgia in a phase 2a study. Methods: We did a double-blind, multicentre, placebo-controlled, randomised withdrawal phase 2a trial in 25 secondary care centres in Denmark, Estonia, France, Germany, Italy, Latvia, Lithuania, Romania, South Africa, Spain, Switzerland, and the UK. After a 7-day run-in phase, eligible patients aged 18–80 years with confirmed trigeminal neuralgia received open-label, BIIB074 150 mg three times per day, orally, for 21 days. Patients who met at least one response criteria were then randomly assigned (1:1) to BIIB074 or placebo for up to 28 days in a double-blind phase. We used an interactive web response system to assign patients with a computer-generated schedule, with stratification (presence or absence of existing pain medication). Patients, clinicians, and assessors were masked to treatment allocation. The primary endpoint was the difference between groups in the number of patients classified as treatment failure during the double blind phase assessed in the modified intention-to-treat population. We assessed safety in all patients who received one or more doses of BIIB074. This study is registered with ClinicalTrials.gov (NCT01540630) and EudraCT (2010-023963-16). Findings: The first patient was enrolled on April 23, 2012, and the last patient completed the study on February 26, 2014. We enrolled 67 patients into the open-label phase; 44 completed open-label treatment, and 29 were randomly assigned to double-blind treatment (15 to BIIB074 and 14 to placebo). During the double-blind phase, five (33%) patients assigned to BIIB074 versus nine (64%) assigned to placebo were classified as treatment failures (p=0·0974). BIIB074 was well tolerated, with similar adverse events in the double-blind phase to placebo. Headache was the most common adverse event with BIIB074 in the open-label phase (in 13 [19%] of 67 patients), followed by dizziness (in six [9%] patients). In the double-blind phase, headache, pyrexia, nasopharyngitis, sleep disorder, and tremor were the most frequent adverse events in patients assigned to BIIB074 (in one [7%] of 15 patients for each event), and headache, dizziness, diarrhoea, and vomiting were the most frequent adverse events in patients assigned to placebo (in one [7%] of 14 patients for each event). No severe or serious adverse events were reported in the BIIB074 group during the double-blind phase. One patient assigned to placebo reported intestinal adhesions with obstruction as a severe and serious adverse event, which was considered as unrelated to study medication. Interpretation: The primary endpoint of treatment failure was not significantly lower in the BIIB074 group than in the placebo group. However, our findings provide a basis for continued investigation of BIIB074 in patients with trigeminal neuralgia in future clinical trials

Olfactory nerve stimulation activates RS cells.

<p>(A) Responses of RS cells following electrical stimulation of the ON with 5 or 15 µA (top versus bottom traces); single shocks or trains of stimulation (left versus right traces). Each trace is a mean of eight individual responses. (B) Calcium fluorescence imaging illustrates the ΔF/F response of identified RS cells to ON stimulation (20 µA –10 Hz). (a, c) ipsilateral. (b, d) contralateral. White scale bar in the photomicrograph represents 100 µm. (C) RS responses to ON electrical stimulation are reduced by glutamate antagonists perfused through the bath (50 µA stimulation, upper traces) (D) or injected onto the OB (50 µA stimulation, bottom traces).</p

Olfactory epithelium stimulation activates RS cells.

<p>(A) Illustration of the experimental procedure in an isolated olfactory epithelium-brain-spinal cord preparation. (B) Responses of RS cell to the application of L-arginine over the olfactory epithelium (Arg, 1 mM). (C) Response to bile acid–taurocholic acid (TCA, 1 µM). (D–E) Responses to male-secreted pheromones, 3-keto-petromyzonol sulfate (3KPZS, 10 µM), and 3-keto allocholic acid (3KACA, 10 µM), respectively. Arrows represent the onset of odor ejection. (B–E) are from different preparations.</p

Schematic representation of the olfactory-locomotor circuitry in lampreys.

<p>Stimulation of the olfactory sensory neurons in the periphery activates neurons in the OB. There are two distinct projections from the OB, one from the lateral and another from the medial part. The lateral part projects to forebrain structures including the lateral pallium, the striatum with some fibers reaching down to habenula (grey arrows). The medial part is the relevant part for generating locomotor behavior. There is a direct projection from the medial part of the OB to the PT. From the PT, there is a projection to the MLR, known to play a crucial role in controlling locomotion in all vertebrate species. MLR neurons project to brainstem reticulospinal neurons, acting as command cells for locomotion. RS cells, in turn, project directly to spinal cord neurons that generate the basic muscle synergies responsible for propulsion during locomotion.</p