Control of Orienting Movements and Locomotion by Projection-Defined Subsets of Brainstem V2a Neurons

International audienceSpatial orientation requires the execution of lateralized movements and a change in the animal's heading in response to multiple sensory modalities. While much research has focused on the circuits for sensory integration, chiefly to the midbrain superior colliculus (SC), the downstream cells and circuits that engage adequate motor actions have remained elusive. Furthermore, the mechanisms supporting trajectory changes are still speculative. Here, using transneuronal viral tracings in mice, we show that brainstem V2a neurons, a genetically defined subtype of glutamatergic neurons of the reticular formation, receive putative synaptic inputs from the contralateral SC. This makes them a candidate relay of lateralized orienting commands. We next show that unilateral optogenetic activations of brainstem V2a neurons in vivo evoked ipsilateral orienting-like responses of the head and the nose tip on stationary mice. When animals are walking, similar stimulations impose a transient locomotor arrest followed by a change of trajectory. Third, we reveal that these distinct motor actions are controlled by dedicated V2a subsets each projecting to a specific spinal cord segment, with at least (1) a lumbar-projecting subset whose unilateral activation specifically controls locomotor speed but neither impacts trajectory nor evokes orienting movements, and (2) a cervical-projecting subset dedicated to head orientation, but not to locomotor speed. Activating the latter subset suffices to steer the animals' directional heading, placing the head orientation as the prime driver of locomotor trajectory. V2a neurons and their modular organization may therefore underlie the orchestration of multiple motor actions during multi-faceted orienting behaviors

Awake perception is associated with dedicated neuronal assemblies in the cerebral cortex

International audienceAbstract Neural activity in the sensory cortex combines stimulus responses and ongoing activity, but it remains unclear whether these reflect the same underlying dynamics or separate processes. In the present study, we show in mice that, during wakefulness, the neuronal assemblies evoked by sounds in the auditory cortex and thalamus are specific to the stimulus and distinct from the assemblies observed in ongoing activity. By contrast, under three different anesthetics, evoked assemblies are indistinguishable from ongoing assemblies in the cortex. However, they remain distinct in the thalamus. A strong remapping of sensory responses accompanies this dynamic state change produced by anesthesia. Together, these results show that the awake cortex engages dedicated neuronal assemblies in response to sensory inputs, which we suggest is a network correlate of sensory perception

Deep imaging in the brainstem reveals functional heterogeneity in V2a neurons controlling locomotion

International audienceV2a neurons are a genetically defined cell class that forms a major excitatory descending pathway from the brainstem reticular formation to the spinal cord. Their activation has been linked to the termination of locomotor activity based on broad optogenetic manipulations. However, because of the difficulties involved in accessing brainstem structures for in vivo cell type–specific recordings, V2a neuron function has never been directly observed during natural behaviors. Here, we imaged the activity of V2a neurons using micro-endoscopy in freely moving mice. We find that as many as half of the V2a neurons are excited at locomotion arrest and with low reliability. Other V2a neurons are inhibited at locomotor arrests and/or activated during other behaviors such as locomotion initiation or stationary grooming. Our results establish that V2a neurons not only drive stops as suggested by bulk optogenetics but also are stratified into subpopulations that likely contribute to diverse motor patterns

The phosphodiesterase inhibitor, ibudilast, attenuates neuroinflammation in the MPTP model of Parkinson’s disease

<div><p>Background/Aims</p><p>Since the degeneration of the nigrostriatal dopaminergic pathway in Parkinson’s disease (PD) is associated with the inflammation process and decreased levels of cyclic nucleotides, inhibition of up-regulated cyclic nucleotide phosphodiesterases (PDEs) appears to be a promising therapeutic strategy. We used ibudilast (IBD), a non-selective PDE3,4,10,11 inhibitor, due to the abundant PDE 4 and 10 expression in the striatum. The present study for the first time examined the efficacy of IBD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.</p><p>Methods</p><p>IBD [0, 20, 30, 40, or 50 mg/kg] was injected b.i.d. subcutaneously for nine days to three-month-old male C57Bl/10Tar mice, beginning two days prior to MPTP (60 mg/kg) intoxication. High-pressure liquid chromatography, Western blot analysis, and real time RT-PCR methods were applied.</p><p>Results</p><p>Our study demonstrated that chronic administration of IBD attenuated astroglial reactivity and increased glial cell-derived neurotrophic factor (GDNF) production in the striatum. Moreover, IBD reduced TNF-α, IL-6, and IL-1β expression.</p><p>Conclusion</p><p>IBD had a well-defined effect on astroglial activation in the mouse model of PD; however, there was no protective effect in the acute phase of injury. Diminished inflammation and an increased level of GDNF may provide a better outcome in the later stages of neurodegeneration.</p></div

Protein expression of (A) GFAP and (B) Iba1 in the striatum, evaluated by immunoblot analysis.

<p>Abbreviations of groups of animals: control–saline-treated; PEG–vehicle-treated; MPTP–MPTP-intoxicated; i(20, 30, 40, or 50)+MPTP–IBD [20, 30, 40, or 50 mg/kg] and MPTP-treated; i(20, 30, 40 or 50)–IBD [20, 30, 40, or 50 mg/kg] treated. The values are expressed as mean ± SEM, for five mice per group (* represents a significant difference relative to control group, **p<0.01; ^# represents a significant difference compared with the MPTP group, ^#p<0.05; Mann Whitney <i>U</i> test).</p

A spatial code for temporal cues is necessary for sensory learning

The temporal structure of sensory inputs contains essential information for their interpretation by the brain 1-9. Sensory systems represent these temporal cues through two codes: the temporal sequences of neuronal activity and the spatial patterns of neuronal firing rate 3,7,10-20. However, it is still unknown which of these two coexisting codes causally drives sensory decisions 3,10,20,21. To separate their contributions, we designed an optogenetic stimulation paradigm in the mouse auditory cortex to generate neuronal activity patterns differing exclusively along their temporal or spatial dimensions. Training mice to discriminate these patterns shows that they efficiently learn to discriminate spatial but not temporal patterns, indicating that spatial representations are necessary for sensory learning. In line with this result, we observed, based on large-scale neuronal recordings of the auditory system, that the auditory cortex is the first region in which spatial patterns efficiently represent temporal auditory cues varying over several hundred milliseconds. This feature is shared by the deep layers of neural networks trained to categorise time-varying sounds. Therefore, the emergence of a spatial code for temporal sensory cues is a necessary condition to associate temporally structured stimuli to decisions. We expect this constraint to be crucial for re-engineering perception by cortical stimulation

Effect of IBD on mRNA expression of pro-inflammatory cytokines and a trophic factor (GDNF).

<p>The mRNA expression of (A) TNF-α, (B) IL-1β, (C) IL-6, and (D) GDNF in the striatum was examined by real time RT-PCR. Abbreviations of groups of animals: control–saline-treated; PEG–vehicle-treated; MPTP–MPTP-intoxicated; i(20, 30, 40, or 50)+MPTP–IBD [20, 30, 40, or 50 mg/kg] and MPTP-treated; i(20, 30, 40, or 50)–IBD [20, 30, 40, or 50 mg/kg] treated. Data is given as the mean value ± SEM of five animals per group (* represents a significant difference relative to the control group, *p<0.05, **p<0.01; ^# represents a significant difference compared with the MPTP group, ^#p<0.05, ^##p<0.01; ^¤ differs from vehicle-treated animals, ^¤p<0.05, ^¤¤p<0.01. Mann Whitney <i>U</i> test).</p

Effect of IBD on the injured nigrostriatal system seven days after MPTP intoxication.

<p>(A) DA concentration in the striata of C57Bl/10Tar mice, measured by HPLC. (B) The ratio of DOPAC to DA and (C) the ratio of final DA metabolite (HVA) to DA indicate the DA turnover rate. (D) Expression of tyrosine hydroxylase (TH) (the rate-limiting enzyme in catecholamine synthesis) in mice striatum was evaluated by Western blot analysis, and (E) one representative blot is shown of five independent experiments. Abbreviations of groups of animals: control–saline-treated; PEG–vehicle-treated; MPTP–MPTP-intoxicated; i(20, 30, 40, or 50)+MPTP–IBD [20, 30, 40, or 50 mg/kg] and MPTP-treated; i(20, 30, 40, or 50)–IBD [20, 30, 40, or 50 mg/kg] treated. The data are shown as means ± SEM (n = 5–6) (* represents a significant difference relative to the control group, *p<0.05, **p<0.01; Mann Whitney <i>U</i> test).</p