Dopamine D2 receptors (D2Rs) in the nucleus accumbens (NAc) regulate motivated behavior, but the underlying neurobiological mechanisms remain unresolved. Here, we show that selective upregulation of D2Rs in the indirect pathway of the adult NAc enhances the willingness to work for food. Mechanistic studies in brain slices reveal that D2R upregulation attenuates inhibitory transmission at two main output projections of the indirect pathway, the classical long-range projections to the ventral pallidum (VP), as well as local collaterals to direct pathway medium spiny neurons. In vivo physiology confirms the reduction in indirect pathway inhibitory transmission to the VP, and inhibition of indirect pathway terminals to VP is sufficient to enhance motivation. In contrast, D2R upregulation in the indirect pathway does not disinhibit neuronal activity of the direct pathway in vivo. These data suggest that D2Rs in ventral striatal projection neurons promote motivation by weakening the canonical output to the ventral pallidum.

Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/ β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4 + T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.blood-brain barrier | endothelial cell | Wnt/β-catenin signaling | MS | EAE I n both multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), leukocytes infiltrate the central nervous system (CNS) across a damaged blood-brain barrier (BBB) to mediate myelin destruction and neuronal damage (1). BBB breakdown is a contributing factor to the pathogenesis of both MS and EAE (2-4). Structural and functional BBB degradation precedes lesion development in both MS and EAE (5-9), and focal BBB abnormalities correlate with clinical exacerbations in the relapsing-remitting form of MS (10). Moreover, BBB leakage precedes the entry of T cells and monocytes into the brain parenchyma (7, 11) and coincides with early infiltration of neutrophils before the onset of EAE (12). Although the severity of barrier leakage decreases over time for most relapsing-remitting MS lesions, as assessed by gadoliniumenhancing magnetic resonance imaging (7, 13-15), whether BBB recovery is an active process and, if so, which pathways mediate its repair, remain unclear.The BBB achieves its highly selective permeability through the presence of (i) tight junctions (TJs) that prevent paracellular diffusion of small molecules and immune cells between endothelial cells (ECs), (ii) very few endocytotic vesicles that restrict movement of large mo...

Summary In multiple sclerosis (MS), soluble tumor necrosis factor (TNF) is detrimental via activation of TNF receptor 1 (TNFR1), whereas transmembrane TNF is beneficial primarily by activating TNF receptor 2 (TNFR2). Here we investigate the role of TNFR2 in microglia and monocytes/macrophages in experimental autoimmune encephalomyelitis (EAE), a model of MS, by cell-specific gene targeting. We show that TNFR2 ablation in microglia leads to early onset of EAE with increased leukocyte infiltration, T cell activation, and demyelination in the central nervous system (CNS). Conversely, TNFR2 ablation in monocytes/macrophages results in EAE suppression with impaired peripheral T cell activation, and reduced CNS T cell infiltration and demyelination. Our work uncovers a dichotomy of function for TNFR2 in myeloid cells, with microglial TNFR2 providing protective signals to contain disease, and monocyte/macrophagic TNFR2 driving immune activation and EAE initiation. This must be taken into account when targeting TNFR2 for therapeutic purposes in neuroinflammatory diseases.

Objective: To evaluate whether multiple sessions of transcranial direct current stimulation (tDCS) applied to the primary motor (M1) cortex paired with aerobic exercise can improve walking functions in multiple sclerosis (MS). Methods: MS participants were recruited for a double-blind, parallel-arm, randomized, sham-controlled trial and assigned to 10 sessions (5 d/wk for 2 weeks) of either active or sham tDCS paired with unloaded cycling for 20 minutes. Stimulation was administered over the left M1 cortex (2.5 mA; anode over C3/cathode over FP2). Gait spatiotemporal parameters were assessed using a wearable inertial sensor (10-meter and 2-minute walking tests). Measurements were collected at baseline, end of tDCS intervention, and 4-week postintervention to test for duration of any benefits. Results: A total of 15 participants completed the study, nine in the active and six in the sham condition. The active and sham groups were matched according to gender (50% vs. 40% female), neurologic disability (median EDSS 5.5 vs. 5), and age (mean 52.1 AE 12.9 vs. 53.7 AE 9.8 years). The active group had a significantly greater increase in gait speed (0.87 vs. 1.20 m/s, p < 0.001) and distance covered during the 2-minute walking test (118.53 vs. 133.06 m, p < 0.001) at intervention end compared to baseline. At 4-week follow-up, these improvements were maintained (baseline vs. follow-up: gait speed 0.87 vs. 1.18 m/s, p < 0.001; distance traveled 118.53 vs. 143.82 m, p < 0.001). Interpretation: Multiple sessions of tDCS paired with aerobic exercise lead to cumulative and persisting improvements in walking and endurance in patients with MS.

Walking impairments are a debilitating feature of multiple sclerosis (MS) because of the direct interference with daily activity. The management of motor symptoms in those with MS remains a therapeutic challenge. Transcranial direct current stimulation (tDCS) is a type of non-invasive brain stimulation that is emerging as a promising rehabilitative tool but requires further characterization to determine its optimal therapeutic use. In this randomized, sham-controlled proof-of-concept study, we tested the immediate effects of a single tDCS session on walking and functional mobility in those with MS. Seventeen participants with MS completed one 20-min session of aerobic exercise, randomly assigned to be paired with either active (2.5 mA, n = 9) or sham (n = 8) tDCS over the primary motor cortex (M1). The groups (active vs. sham) were matched according to gender (50% vs. 60% F), age (52.1 ± 12.85 vs. 54.2 ± 8.5 years), and level of neurological disability (median Expanded Disability Status Scale score 5.5 vs. 5). Gait speed on the 10-m walk test and the Timed Up and Go (TUG) time were measured by a wearable inertial sensor immediately before and following the 20-min session, with changes compared between conditions and time. There were no significant differences in gait speed or TUG time changes following the session in the full sample or between the active vs. sham groups. These findings suggest that a single session of anodal tDCS over M1 is not sufficient to affect walking and functional mobility in those with MS. Instead, behavioral motor response of tDCS is likely to be cumulative, and the effects of multiple tDCS sessions require further study.