Brainstem circuits involved in skilled forelimb movements

Movement is the main output of the nervous system as well as the fundamental form of interaction animals have with their environment. Due to its function and scope, movement has to be characterized by both stability and flexibility. Such apparently conflicting attributes are reflected in the complex organization of the motor system, composed of a vast network of widely distributed circuits interacting with each other to generate an appropriate motor output. Different neuronal structures, located throughout the brain, are responsible for producing a broad spectrum of actions, ranging from simple locomotion to complex goal directed movements such as reaching for food or playing a musical instrument. The brainstem is one of such structures, holding considerable importance in the generation of the motor output, but also largely unexplored, due to its less-than-accessible anatomic location, functional intricacies and the lack of appropriate techniques to investigate its complexity. Despite recent advances, a deeper understanding of the role of brainstem neuronal circuits in skilled movements is still missing. In this dissertation, we investigated the involvement of the lateral rostral medulla (LatRM) in the construction of skilled forelimb behaviors. The focus of my work was centered on elucidating the anatomical and functional relationships between LatRM and the caudal brainstem, and specifically on the interactions with the medullary reticular formation, considering both its ventral (MdV) and dorsal subdivisions (MdD). In summary, we reveal the existence of anatomically segregated subpopulations of neurons in the lower brainstem which encode different aspects of skilled forelimb movements. Moreover, we show that LatRM neurons are necessary for the correct execution of skilled motor programs and their activation produces complex coordinated actions. All this evidence suggests that LatRM may be a key orchestrator for skilled movements by functioning as integration center for upstream signals as well as coordinator by selecting the appropriate effectors in the lower medulla and the spinal cord

Loss of Mecp2 causes atypical synaptic and molecular plasticity of parvalbumin-expressing interneurons reflecting rett syndrome–like sensorimotor defects

Rett syndrome (RTT) is caused in most cases by loss-of-function mutations in the X-linked gene encoding methyl CpG-binding protein 2 (MECP2). Understanding the pathological processes impacting sensory-motor control represents a major challenge for clinical management of individuals affected by RTT, but the underlying molecular and neuronal modifications remain unclear. We find that symptomatic male Mecp2 knockout (KO) mice show atypically elevated parvalbumin (PV) expression in both somatosensory (S1) and motor (M1) cortices together with excessive excitatory inputs converging onto PV-expressing interneurons (INs). In accordance, high-speed voltage-sensitive dye imaging shows reduced amplitude and spatial spread of synaptically induced neuronal depolarizations in S1 of Mecp2 KO mice. Moreover, motor learning-dependent changes of PV expression and structural synaptic plasticity typically occurring on PV+ INs in M1 are impaired in symptomatic Mecp2 KO mice. Finally, we find similar abnormalities of PV networks plasticity in symptomatic female Mecp2 heterozygous mice. These results indicate that in Mecp2 mutant mice the configuration of PV+ INs network is shifted toward an atypical plasticity state in relevant cortical areas compatible with the sensory-motor dysfunctions characteristics of RTT.Rett syndrome (RTT) is caused in most cases by loss-of-function mutations in the X-linked gene encoding methyl CpG-binding protein 2 (MECP2). Understanding the pathological processes impacting sensory-motor control represents a major challenge for clinical management of individuals affected by RTT, but the underlying molecular and neuronal modifications remain unclear. We find that symptomatic male Mecp2 knockout (KO) mice show atypically elevated parvalbumin (PV) expression in both somatosensory (S1) and motor (M1) cortices together with excessive excitatory inputs converging onto PV-expressing interneurons (INs). In accordance, high-speed voltage-sensitive dye imaging shows reduced amplitude and spatial spread of synaptically induced neuronal depolarizations in S1 of Mecp2 KO mice. Moreover, motor learning-dependent changes of PV expression and structural synaptic plasticity typically occurring on PV + INs in M1 are impaired in symptomatic Mecp2 KO mice. Finally, we find similar abnormalities of PV networks plasticity in symptomatic female Mecp2 heterozygous mice. These results indicate that in Mecp2 mutant mice the configuration of PV + INs network is shifted toward an atypical plasticity state in relevant cortical areas compatible with the sensory-motor dysfunctions characteristics of RTT

A functional map for diverse forelimb actions within brainstem circuitry

The brainstem is a key centre in the control of body movements. Although the precise nature of brainstem cell types and circuits that are central to full-body locomotion are becoming known; 1-5; , efforts to understand the neuronal underpinnings of skilled forelimb movements have focused predominantly on supra-brainstem centres and the spinal cord; 6-12; . Here we define the logic of a functional map for skilled forelimb movements within the lateral rostral medulla (latRM) of the brainstem. Using in vivo electrophysiology in freely moving mice, we reveal a neuronal code with tuning of latRM populations to distinct forelimb actions. These include reaching and food handling, both of which are impaired by perturbation of excitatory latRM neurons. Through the combinatorial use of genetics and viral tracing, we demonstrate that excitatory latRM neurons segregate into distinct populations by axonal target, and act through the differential recruitment of intra-brainstem and spinal circuits. Investigating the behavioural potential of projection-stratified latRM populations, we find that the optogenetic stimulation of these populations can elicit diverse forelimb movements, with each behaviour stably expressed by individual mice. In summary, projection-stratified brainstem populations encode action phases and together serve as putative building blocks for regulating key features of complex forelimb movements, identifying substrates of the brainstem for skilled forelimb behaviours