INDUCING REPRESENTATIONAL CHANGE IN THE HIPPOCAMPUS THROUGH REAL-TIME NEUROFEEDBACK.

When you perceive or remember one thing, other related things come to mind. This competition has consequences for how these items are later perceived, attended, or remembered. Such behavioral consequences result from changes in how much the neural representations of the items overlap, especially in the hippocampus. These changes can reflect increased (integration) or decreased (differentiation) overlap; previous studies have posited that the amount of coactivation between competing representations in cortex determines which will occur: high coactivation leads to hippocampal integration, medium coactivation leads to differentiation, and low coactivation is inert. However, those studies used indirect proxies for coactivation, by manipulating stimulus similarity or task demands. Here we induce coactivation of competing memories in visual cortex more directly using closed-loop neurofeedback from real-time fMRI. While viewing one object, participants were rewarded for implicitly activating the representation of another object as strongly as possible. Across multiple real-time fMRI training sessions, they succeeded in using the neurofeedback to induce coactivation. Compared with untrained objects, this coactivation led to behavioral and neural integration: The trained objects became harder for participants to discriminate in a categorical perception task and harder to decode from patterns of fMRI activity in the hippocampus.

Global and subtype-specific modulation of cortical inhibitory neurons regulated by acetylcholine during motor learning.

Inhibitory neurons (INs) consist of distinct subtypes with unique functions. Previous studies on INs mainly focused on single brain regions, and thus it remains unclear whether the modulation of IN subtypes occurs globally across multiple regions. Here, we monitored the activity of different cortical IN subtypes at both macroscale and microscale in mice learning a lever-press task. Learning evoked a global modulation of IN subtypes throughout the cortex. The initial learning phase involved strong activation of vasoactive intestinal peptide-expressing INs (VIP-INs) and weak activation of somatostatin-expressing INs (SOM-INs). Inactivating VIP-INs increased SOM-IN activity and impaired initial learning. Concurrently, cortical cholinergic inputs from the basal forebrain were initially more active but became less engaged over learning. Manipulation of the cholinergic system impaired motor learning and differentially altered activity of IN subtypes. These results reveal that motor learning involves a global and subtype-specific modulation on cortical INs regulated by the cholinergic system.

Knockdown of genes involved in axonal transport enhances the toxicity of human neuromuscular disease-linked MATR3 mutations in Drosophila.

Mutations in the nuclear matrix protein Matrin 3 (MATR3) have been identified in amyotrophic lateral sclerosis and myopathy. To investigate the mechanisms underlying MATR3 mutations in neuromuscular diseases and efficiently screen for modifiers of MATR3 toxicity, we generated transgenic MATR3 flies. Our findings indicate that expression of wild-type or mutant MATR3 in motor neurons reduces climbing ability and lifespan of flies, while their expression in indirect flight muscles (IFM) results in abnormal wing positioning and muscle degeneration. In both motor neurons and IFM, mutant MATR3 expression results in more severe phenotypes than wild-type MATR3, demonstrating that the disease-linked mutations confer pathogenicity. We conducted a targeted candidate screen for modifiers of the MATR3 abnormal wing phenotype and identified multiple enhancers involved in axonal transport. Knockdown of these genes enhanced protein levels and insolubility of mutant MATR3. These results suggest that accumulation of mutant MATR3 contributes to toxicity and implicate axonal transport dysfunction in disease pathogenesis.