The anterior lateral motor cortex (ALM) is critical to subsequent correct movements and plays a vital role in predicting specific future movements. Different descending pathways of the ALM are preferentially involved in different roles in movements. However, the circuit function mechanisms of these different pathways may be concealed in the anatomy circuit. Clarifying the anatomy inputs of these pathways should provide some helpful information for elucidating these function mechanisms. Here, we used a retrograde trans-synaptic rabies virus to systematically generate, analyze, and compare whole brain maps of inputs to the thalamus (TH)-, medulla oblongata (Med)-, superior colliculus (SC)-, and pontine nucleus (Pons)-projecting ALM neurons in C57BL/6J mice. Fifty-nine separate regions from nine major brain areas projecting to the descending pathways of the ALM were identified. Brain-wide quantitative analyses revealed identical whole brain input patterns between these descending pathways. Most inputs to the pathways originated from the ipsilateral side of the brain, with most innervations provided by the cortex and TH. The contralateral side of the brain also sent sparse projections, but these were rare, emanating only from the cortex and cerebellum. Nevertheless, the inputs received by TH-, Med-, SC-, and Pons-projecting ALM neurons had different weights, potentially laying an anatomical foundation for understanding the diverse functions of well-defined descending pathways of the ALM. Our findings provide anatomical information to help elucidate the precise connections and diverse functions of the ALM.NEW & NOTEWORTHY Distinct descending pathways of anterior lateral motor cortex (ALM) share common inputs. These inputs are with varied weights. Most inputs were from the ipsilateral side of brain. Preferential inputs were provided by cortex and thalamus (TH).

Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC) involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Peripheral neuropathy was induced by unilateral spinal nerve ligation in the rat with a chronic intracerebral and intrathecal catheter for drug administrations. Mechanical hypersensitivity in the injured limb was assessed by monofilaments. Heat nociception was assessed by determining radiant heat-induced paw flick. Histamine in the LC produced a dose-related (1-10μg) mechanical antihypersensitivity effect (maximum effect at 15min and duration of effect 30min), without influence on heat nociception. Pretreatment of LC with zolantidine (histamine H2 receptor antagonist), but not with pyrilamine (histamine H1 receptor antagonist), and spinal administration of atipamezole (an α2-adrenoceptor antagonist), prazosine (an α1-adrenoceptor antagonist) or bicuculline (a GABAA receptor antagonist) attenuated the antihypersensitivity effect of histamine. The histamine-induced antihypersensitivity effect was also reduced by pretreatment of LC with fadolmidine, an α2-adrenoceptor agonist inducing autoinhibition of noradrenergic cell bodies. Zolantidine or pyrilamine alone in the LC failed to influence pain behavior, while A-960656 (histamine H3 receptor antagonist) suppressed hypersensitivity. A plausible explanation for these findings is that histamine, due to excitatory action mediated by the histamine H2 receptor on noradrenergic cell bodies, promotes descending spinal α1/2-adrenoceptor-mediated inhibition of neuropathic hypersensitivity. Blocking the autoinhibitory histamine H3 receptor on histaminergic nerve terminals in the LC facilitates release of histamine and thereby, increases descending noradrenergic pain inhibition.