Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits

Abstract

Ramanathan DS, Conner JM, Anilkumar AA, Tuszynski MH. Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits. J Neurophysiol 113: 1585-1597, 2015. First published December 10, 2014 doi:10.1152/jn.00408.2014.-Previous studies reported that early postnatal cholinergic lesions severely perturb early cortical development, impairing neuronal cortical migration and the formation of cortical dendrites and synapses. These severe effects of early postnatal cholinergic lesions preclude our ability to understand the contribution of cholinergic systems to the later-stage maturation of topographic cortical representations. To study cholinergic mechanisms contributing to the later maturation of motor cortical circuits, we first characterized the temporal course of cortical motor map development and maturation in rats. In this study, we focused our attention on the maturation of cortical motor representations after postnatal day 25 (PND 25), a time after neuronal migration has been accomplished and cortical volume has reached adult size. We found significant maturation of cortical motor representations after this time, including both an expansion of forelimb representations in motor cortex and a shift from proximal to distal forelimb representations to an extent unexplainable by simple volume enlargement of the neocortex. Specific cholinergic lesions placed at PND 24 impaired enlargement of distal forelimb representations in particular and markedly reduced the ability to learn skilled motor tasks as adults. These results identify a novel and essential role for cholinergic systems in the late refinement and maturation of cortical circuits. Dysfunctions in this system may constitute a mechanism of late-onset neurodevelopmental disorders such as Rett syndrome and schizophrenia.

Perinatal nicotine exposure impairs the maturation of glutamatergic inputs in the auditory brainstem

“…; Ramanathan et al . ). However, these experiments mostly relied on the deletion of specific nAChR subtypes or on disruption of cholinergic inputs to the target cells which in both cases reduces cholinergic signalling.…”

“…To our surprise the pruning of excitatory inputs to VNLL neurons was not diminished in nicotine-treated mice. A direct link between nAChRs and synaptic remodelling has been suggested for a number of cortical neural circuits (Liu et al 2007;Lozada et al 2012;Ramanathan et al 2015). However, these experiments mostly relied on the deletion of specific nAChR subtypes or on disruption of cholinergic inputs to the target cells which in both cases reduces cholinergic signalling.…”

Monoaminergic Modulation of Motor Cortex Function

“…More recently, the key role of acetylcholine in motor skill learning has been more closely investigated. Indeed, acetylcholine modulates the reorganization of cortical maps following motor training (Conner et al, 2003 , 2010 ; Ramanathan et al, 2009 , 2015 ). Moreover, muscarinic receptors have been shown to be involved in motor cortex activity and plasticity (Desai and Walcott, 2006 ; Tian et al, 2014 ; Hedrick and Waters, 2015 ).…”

Graded Arrays of Spinal and Supraspinal V2a Interneuron Subtypes Underlie Forelimb and Hindlimb Motor Control

“…The sites of motor computations appear to be distributed across many areas of the CNS, making it challenging to identify the origin of body part-specific movements. Microstimulation and anatomical studies have shown that higher-level (supraspinal) circuitry contributes to the computations necessary to generate motor commands appropriate for particular body segments (Esposito et al, 2014;Graziano et al, 2002;Harrison et al, 2012;Jeffery and Fitzgerald, 1999;Ramanathan et al, 2015;Tennant et al, 2012). In addition to supraspinal structures, the spinal cord itself is a major site for computing motor actions at each level of the body (Bizzi et al, 1991;H€ agglund et al, 2013;Juvin et al, 2005;Levine et al, 2014;Ruder et al, 2016).…”