Compensatory Relearning Following Stroke: Cellular and Plasticity Mechanisms in Rodents

Abstract

von Monakow's theory of diaschisis states the functional 'standstill' of intact brain regions that are remote from a damaged area, often implied in recovery of function. Accordingly, neural plasticity and activity patterns related to recovery are also occurring at the same regions. Recovery relies on plasticity in the periinfarct and homotopic contralesional regions and involves relearning to perform movements. Seeking evidence for a relearning mechanism following stroke, we found that rodents display many features that resemble classical learning and memory mechanisms. Compensatory relearning is likely to be accompanied by gradual shaping of these regions and pathways, with participating neurons progressively adapting cortico-striato-thalamic activity and synaptic strengths at different cortico-thalamic loops - adapting function relayed by the striatum. Motor cortex functional maps are progressively reinforced and shaped by these loops as the striatum searches for different functional actions. Several cortical and striatal cellular mechanisms that influence motor learning may also influence post-stroke compensatory relearning. Future research should focus on how different neuromodulatory systems could act before, during or after rehabilitation to improve stroke recovery.

Keywords: motor learning; pharmacotherapy; plasticity; rehabilitation; stroke.

FIGURE 1

Pronounced intra-cortical connectivity and redundancy are remarkable features of the motor cortex. Motor cortex caudal (e.g., cortical region I) and rostral (e.g., cortical region II) forelimb areas contain the primary motor neurons that encode motor map representations of forelimb skilled movements. Pyramidal neurons project to brainstem and spinal cord (not shown) and send collaterals to striatum and thalamus – integrating thalamo-cortico-thalamic and thalamo-cortico striatal loops. (1) widespread thalamo-cortical connections common to both cortical regions (I and II) target superficial layers and reach damaged, periinfarct and spared areas (upper green and blue solid lines); (2) the preamplifier-like network (green circular loop) captures thalamic I signals and drives output neurons in lower layers (Weiler et al., 2008); (3) horizontal cortico-cortical connections of neurons receive and retransmit this indirect thalamic information (previously shared with the infarct core area) (green solid lines); (4) cortico-thalamic and cortico-striatal projections (from cortical region I to II; gray solid line) integrate another striatal-thalamo-cortical loop (cortical region II). The putative participation of crossed cortico-striatal and cortico-cortical fibers is shown (hashed black lines, bottom right). (5) Cells from adjacent/spared tissue (cortical region II) share thalamo-cortical inputs with interconnected/intertwined thalamo-cortical circuits of the stroke-disrupted network to control compensatory relearning of movements. GP, globus pallidus; SN, substantia nigra.

FIGURE 2

Neuromodulation: main cortical neurotransmitter systems involved in motor learning. (A) Glutamate release from cortical or thalamic afferents can modulate cellular excitability and short/long-term plasticity in cortical pyramidal neurons. Metabotropic glutamate receptors (mGlu₅Rs) are mainly expressed in cortical layer V and act via G_q/O protein on downstream targets. This interaction can enhance NMDARs activity and induce LTP in pyramidal neurons. (B) Raphe nucleus serotonin (5-HT) can bind to 5-HT_1ARs (high mRNA expression in cortical layers V and VI) and via a G_iα protein-AC5/6 pathway induce K⁺ efflux leading to cell hyperpolarization, both in pyramidal cells and FS interneurons. (C) Nucleus basalis acetylcholine (ACh) binds to muscarinic receptors (MRs; e.g., m₄Rs) or nicotinic receptors (NRs). m₄Rs are expressed in all cortical layers and are coupled to G_i proteins that can reduce cellular activity through cAMP signaling. NMDARs are permeable to Na⁺, K⁺, and Ca²⁺ ions and are modulated by intra- and extra-Ca²⁺ concentrations (not shown). (D,E) Dopamine (DA) released by the midbrain dopaminergic system can bind to D₁Rs (low expression in layers II–III and high expression in layers V–VI) or D₂Rs (expressed in layer V but at a lower extent when compared to D₁ expression) and increase or decrease cellular excitability, respectively, via cAMP acting on downstream targets (e.g., DARPP32). (F) Locus coeruleus noradrenaline (NA) released to the cerebral cortex binds to adrenoceptors (ARs) highly expressed in cortical layers IV and V. NA may increase cortical excitability via a reduction of outward K⁺ currents and increase of Na⁺ currents. (G) Simplified model of cortical neurotransmitter systems involved in motor learning.

FIGURE 3

Striatal cellular and synaptic organization. (A) Striatum is a single structure in rodents: see striatal theoretical compartmentalization into dorsolateral (red; putamen) and medial (blue; caudate) striatum (Hjornevik, 2007; Heilbronner et al., 2016). Early and late skill learning are suggested to occur in a mediolateral fashion, respectively. (A, lower panels) In rodents the main thalamo-striatal afferents originate from the parafascicular nucleus. (B) The striatal circuit is composed of several intertwined structures involved in inhibition (indirect-pathway) or disinhibition (direct-pathway) of movement. The indirect-pathway (blue arrows) is formed by striatopallidal MSNs (iMSNs) that project to GABAergic pallidal neurons (external globus pallidus), which exert a powerful inhibitory control into proximal dendrites of glutamatergic neurons in the subthalamic nucleus. Subthalamic nucleus neurons send excitatory afferents to inhibitory output neurons of substantia nigra, and also to internal globus pallidus neurons. The net effect of indirect-pathway activation is inhibition of thalamo-cortical projection neurons, which can reduce cortical premotor drive and inhibit movement. The direct-pathway circuit (green arrows) is formed by striatonigral medium spiny neurons (dMSNs) that provides mainly inhibitory inputs to both GABAergic and dopaminergic cells in substantia nigra, which in turn sends axons to motor nuclei of the thalamus. Direct-pathway activation results in disinhibition of excitatory thalamo-cortical projections, resulting in activation of cortical premotor circuits and the selection/facilitation of movement. Glutamatergic striatal inputs from all cortical areas massively converge into the striatum. Also note the long-range GABAergic projections from the motor cortex to the dorsal striatum. Cortico-striatal and thalamo-striatal glutamatergic inputs target MSNs, large cholinergic interneurons and fast spiking interneurons. Cortico-striatal projections receive several inputs and integrate this information into striatal target neurons. Cholinergic interneurons receive scattered excitatory innervation mainly from thalamus and inhibitory synapses from MSNs. ‘Up-states’ are modulated by intrastriatal acetylcholine (ACh) and to strong intra-striatal DA release, D₁Rs activation and striatal LTP. Midbrain dopaminergic terminals release dopamine (DA), which exerts a massive effect on all striatal cells. “Down-states” are associated to reduced intra-striatal DA, D₁Rs/D₂Rs activation and striatal LTD. Striatal LTP/LTD is also dependent on NMDARs activation and Ca²⁺ influx in MSNs. (B, right panels) Also note the distribution of cortico-striatal and thalamo-striatal afferents (Hunnicutt et al., 2016). (C) Long-term depression is dependent on mGLU_1/5Rs, D₂Rs, M₁Rs, and C₁BRs. For example, in iMSNs, prolonged stimulation of excitatory afferents paired with post-synaptic depolarization triggers the production and release of eCBs (e.g., 2AG) from the precursor diacylglycerol (DAG) through the activation of mGlu_1/5Rs and phospholipase C (PLC; this process is dependent on Ca²⁺). (D) Long-term potentiation is dependent on NMDARs, D₁Rs, A2ARs and CB₁Rs. LTP is NMDARs dependent and is likely to involve the exocytosis of AMPA receptors. For example, LTP in the indirect pathway is negatively regulated by D₂Rs (dependent on extracellular regulated kinase; ERK) and positively regulated by adenosine A2ARs.

FIGURE 4

Motor learning and post-stroke relearning. (A, upper and middle panels) Motor learning is divided into a fast phase, with rapid improvement in performance, and a slow phase related to a “cortical learning mode” likely involved in the consolidation of motor skills. After 8–10 days of training the motor skill is acquired and transient changes imply in motor map expansion-renormalization according to the trained skill (Kleim et al., 2003; Molina-Luna et al., 2008; Wenger et al., 2017). (A, lower panel) The motor map/engram is composed by the motor map of the acquired skill and by specific cortico-striatal-thalamo-cortical loops (green). (B, left panels) From top to bottom, the respective motor map (green) is sustained by specific cortico-striatal-thalamo-cortical loops following motor map expansion-renormalization related to the acquired skill. The loop diagram describes the ipsilesional (black lines) and crossed (black hashed lines) connections from specific cortical, striatal and thalamic regions I and II (bottom). (B, middle and right panels) From top to bottom, post-stroke, diaschisis may affect motor representations with, respectively, impaired skilled function. The lesion core is surrounded by dysfunctional tissue, such as periinfarct tissue (orange) and regions of focal and non-focal diaschisis (blue). Connectivity is changed and the putative participation of adjacent cortico-striatal-thalamo-cortical loops in the ipsi- and contralesional hemispheres is shown. Cortical stroke (red cross and connections) induces cellular and plastic changes (blue arrows and letters). Post-stroke cellular and plastic changes during relearning of the skilled movements may also occur in a medial to lateral fashion, similarly to motor learning and may include: increased activity in the medial portion of the ipsilesional striatum (gray); increased activity of uncrossed corticospinal fibers and of mirror-image neurons in the contralesional hemisphere (blue lines); increased activation of crossed corticostriatal fibers (blue hashed lines); short- and long-term striatal plasticity that results in increased dendritic branching and spines in the ipsi and contralesional hemispheres; the putative participation of the contralesional medial striatum during later phases of slow relearning; motor maps are reorganized and potentiated corticospinal projections to the affected muscles are available, both in the ipsi and contralesional hemispheres (i.e., crossed and uncrossed corticospinal fibers) (Pruitt et al., 2016). Connections and loops are rearranged and the newly formed motor configurations are encoded into the lateral portions of bilateral striatum. C, cortex; S, striatum; T, thalamus.

FIGURE 5

Diaschisis as a consolidation-reconsolidation process. (A, left) Movement before stroke involves the selection of the appropriate motor program for the specific action (cortico-striatal-thalamo-cortical loops). (A, right) Specific actions are linked to specific cortico-striatal-thalamo-cortical loops. This specific functional region may control a voluntary movement, using the appropriate motor sequence for a coordinated muscular action. (B, left panels) Following stroke, diaschisis of regions close or distant to the infarct core (light blue) affects the functionality of the motor network and disrupts or change the specific action (red arrows: lost connections; blue and black arrows: remaining connections). (B, right panels) This results in loss of upper motor neuron control over voluntary movements and the emergence of abnormal movements (Balbinot et al., 2018). Compensatory relearning is unlikely to fully restitute movements of the paretic limb, which should retain some of the abnormalities and deficits in the specific action. Functional compensatory movements may be reinforced by lateral inhibition between ipsilesional MSNs (solid lines; the striatal region I influence striatal region II) and/or contralesional cortico-striatal connections (hashed lines). This reinforcement is shaped by striatal state changes and cortical plasticity. (C) Rehabilitation provides the recollection of visual, tactile and motor cues: the motor output is a changed action tailored over many rehabilitation sections during the “striatal search task” and the “cortical learning mode”. It is likely that consolidation–reconsolidation mechanisms are slowly acting to shape these circuits during rehabilitation. Compensatory brain regions may supplement function of damaged areas and a novel motor engram is formed (dark blue) (e.g., Kim et al., 2018). The system is shaped toward the specific actions used over rehabilitation sections. Hence, the generation of a novel motor engram is supported by a series of adjustments in connections of the redundant motor system network. Right panels in (A–C) are inspired by a new perspective for striatal local circuitry plasticity (Burke et al., 2017). The authors explore how lateral inhibition (between MSNs) can contribute to the formation of functional units to process, integrate and filter inputs to generate motor patterns and learned behaviors (Burke et al., 2017).