SUMMARY The episodic nature of locomotion is thought to be controlled by descending inputs from the brainstem. Most studies have largely attributed this control to initiating excitatory signals, but little is known about putative commands that may specifically determine locomotor offset. To link identifiable brainstem populations to a potential locomotor stop signal, we used developmental genetics and considered a discrete neuronal population in the reticular formation: the V2a neurons. We find that those neurons constitute a major excitatory pathway to locomotor areas of the ventral spinal cord. Selective activation of V2a neurons of the rostral medulla stops ongoing locomotor activity, owing to an inhibition of premotor locomotor networks in the spinal cord. Moreover, inactivation of such neurons decreases spontaneous stopping in vivo. Therefore, the V2a “stop neurons” represent a glutamatergic descending pathway that favors immobility and may thus help control the episodic nature of locomotion.
SignificanceMaintaining low CO2 levels in our bodies is critical for life and depends on neurons that generate the respiratory rhythm and monitor tissue gas levels. Inadequate response to increasing levels of CO2 is common in congenital hypoventilation diseases. Here, we identified a mutation in LBX1, a homeodomain transcription factor, that causes congenital hypoventilation in humans. The mutation alters the C terminus of the protein without disturbing its DNA-binding domain. Mouse models carrying an analogous mutation recapitulate the disease. The mutation spares most Lbx1 functions, but selectively affects development of a small group of neurons central in respiration. Our work reveals a very unusual pathomechanism, a mutation that hampers a small subset of functions carried out by a transcription factor.
The lateral habenula (LHb) is hyperactive in depression, and thus potentiating inhibition of this structure makes an interesting target for future antidepressant therapies. However, the circuit mechanisms mediating inhibitory signalling within the LHb are not well-known. We addressed this issue by studying LHb neurons expressing either parvalbumin (PV) or somatostatin (SOM), two markers of particular sub-classes of neocortical inhibitory neurons. Here, we find that both PV and SOM are expressed by physiologically distinct sub-classes. Furthermore, we describe multiple sources of inhibitory input to the LHb arising from both local PV-positive neurons, from PV-positive neurons in the medial dorsal thalamic nucleus, and from SOM-positive neurons in the ventral pallidum. These findings hence provide new insight into inhibitory control within the LHb, and highlight that this structure is more neuronally diverse than previously thought.
The lateral septum (LS) has been implicated in the regulation of locomotion. Nevertheless, the neurons synchronizing LS activity with the brain’s clock in the suprachiasmatic nucleus (SCN) remain unknown. By interrogating the molecular, anatomical and physiological heterogeneity of dopamine neurons of the periventricular nucleus (PeVN; A14 catecholaminergic group), we find that Th+/Dat1+ cells from its anterior subdivision innervate the LS in mice. These dopamine neurons receive dense neuropeptidergic innervation from the SCN. Reciprocal viral tracing in combination with optogenetic stimulation ex vivo identified somatostatin-containing neurons in the LS as preferred synaptic targets of extrahypothalamic A14 efferents. In vivo chemogenetic manipulation of anterior A14 neurons impacted locomotion. Moreover, chemogenetic inhibition of dopamine output from the anterior PeVN normalized amphetamine-induced hyperlocomotion, particularly during sedentary periods. Cumulatively, our findings identify a hypothalamic locus for the diurnal control of locomotion and pinpoint a midbrain-independent cellular target of psychostimulants.
22 Phone: +44 (0)141 548 2122 23 24 2 25 Summary: The lateral habenula receives inhibitory input from three distinct sources: 26 from local PV-positive neurons, from PV-positive neurons in the medial dorsal thalamic 27 nucleus (MDT); and from SOM-positive neurons in the ventral pallidum (VP). 28 3 Abstract 29 The lateral habenula (LHb) is hyperactive in depression, and thus potentiating 30 inhibition of this structure makes an interesting target for future antidepressant 31 therapies. However, the circuit mechanisms mediating inhibitory signalling within the 32 LHb are not well-known. We addressed this issue by studying LHb neurons expressing 33 either parvalbumin (PV), neuron-derived neurotrophic factor (Ndnf) or somatostatin 34 (SOM), three markers of particular sub-classes of neocortical inhibitory neurons. While 35 we report that Ndnf is not representative of any particular sub-population of LHb 36 neuron, we find that both PV and SOM are expressed by physiologically distinct sub-37 classes. Furthermore, we describe multiple sources of inhibitory input to the LHb 38 arising from both local PV-positive neurons, and from PV-positive neurons in the 39 medial dorsal thalamic nucleus, and from SOM-positive neurons in the ventral 40 pallidum. These findings hence provide new insight into inhibitory control within the 41 LHb, and highlight that this structure is more neuronally diverse than previously 42 thought. 43 44Significance statement 45 The circuitry by which inhibitory signalling is processed within the lateral habenula is 46 currently not well understood; yet this is an important topic as inhibition of the lateral 47 53We are grateful to Hongkui Zeng from the Allen Brain Institute, Seattle, for kindly 54 sharing the Ai9 reporter mice with us, and we thank Csaba Földy, Brain Research 55
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