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

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

Olfactory inputs are relayed via the PT and MLR.

<p>(A) Schematic illustration showing the experimental procedure where glutamate receptor antagonists were injected in different sites indicated by the arrows. (B) RS cell responses to ON stimulation are strongly decreased by the injection in the PT. (C) Injection in the MLR has a similar effect. (D) An injection in the DLR does not block the synaptic responses. (B, C, D) are from different preparations.</p

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

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

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

Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial

Background: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. Methods: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0–5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. Findings: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88–1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4–10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (&lt;1%) in the control group (RR 4·2; 95% CI 0·9–19·7, p=0·059). Interpretation: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis