Binding During Sequence Learning Does Not Alter Cortical Representations of Individual Actions.

As a sequence of movements is learned, serially ordered actions get bound together into sets to reduce computational complexity during planning and execution. Here, we investigated how actions become naturally bound over the course of learning and how this learning affects cortical representations of individual actions. Across 5 weeks of practice, neurologically healthy human subjects learned either a complex 32-item sequence of finger movements (trained group, n = 9; 3 female) or randomly ordered actions (control group, n = 9; 3 female). Over the course of practice, responses during sequence production in the trained group became temporally correlated, consistent with responses being bound together under a common command. These behavioral changes, however, did not coincide with plasticity in the multivariate representations of individual finger movements, assessed using fMRI, at any level of the cortical motor hierarchy. This suggests that the representations of individual actions remain stable, even as the execution of those same actions become bound together in the context of producing a well learned sequence.SIGNIFICANCE STATEMENT Extended practice on motor sequences results in highly stereotyped movement patterns that bind successive movements together. This binding is critical for skilled motor performance, yet it is not currently understood how it is achieved in the brain. We examined how binding altered the patterns of activity associated with individual movements that make up the sequence. We found that fine finger control during sequence production involved correlated activity throughout multiple motor regions; however, we found no evidence for plasticity of the representations of elementary movements. This suggests that binding is associated with plasticity at a more abstract level of the motor hierarchy.

TrpM8-mediated somatosensation in mouse neocortex.

Somatosensation is a complex sense mediated by more than a dozen distinct neural subtypes in the periphery. Although pressure and touch sensation have been mapped to primary somatosensory cortex in rodents, it has been controversial whether pain and temperature inputs are also directed to this area. Here we use a well-defined somatosensory modality, cool sensation mediated by peripheral TrpM8-receptors, to investigate the neural substrate for cool perception in the mouse neocortex. Using activation of cutaneous TrpM8 receptor-expressing neurons, we identify candidate neocortical areas responsive for cool sensation. Initially, we optimized TrpM8 stimulation and determined that menthol, a selective TrpM8 agonist, was more effective than cool stimulation at inducing expression of the immediate-early gene c-fos in the spinal cord. We developed a broad-scale brain survey method for identification of activated brain areas, using automated methods to quantify c-fos immunoreactivity (fos-IR) across animals. Brain areas corresponding to the posterior insular cortex and secondary somatosensory (S2) show elevated fos-IR after menthol stimulation, in contrast to weaker activation in primary somatosensory cortex (S1). In addition, menthol exposure triggered fos-IR in piriform cortex, the amygdala, and the hypothalamus. Menthol-mediated activation was absent in TrpM8-knock-out animals. Our results indicate that cool somatosensory input broadly drives neural activity across the mouse brain, with neocortical signal most elevated in the posterior insula, as well as S2 and S1. These findings are consistent with data from humans indicating that the posterior insula is specialized for somatosensory information encoding temperature, pain, and gentle touch.

Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels.

Compelling evidence links amyloid beta (Aß) peptide accumulation in the brains of Alzheimer's disease (AD) patients with the emergence of learning and memory deficits, yet a clear understanding of the events that drive this synaptic pathology are lacking. We present evidence that neurons exposed to Aß are unable to form new synapses, resulting in learning deficits in vivo. We demonstrate the Nogo receptor family (NgR1-3) acts as Aß receptors mediating an inhibition of synapse assembly, plasticity, and learning. Live imaging studies reveal Aß activates NgRs on the dendritic shaft of neurons, triggering an inhibition of calcium signaling. We define T-type calcium channels as a target of Aß-NgR signaling, mediating Aß's inhibitory effects on calcium, synapse assembly, plasticity, and learning. These studies highlight deficits in new synapse assembly as a potential initiator of cognitive pathology in AD, and pinpoint calcium dysregulation mediated by NgRs and T-type channels as key components. VIDEO ABSTRACT.

Differentiating Visual from Response Sequencing during Long-term Skill Learning.

The dual-system model of sequence learning posits that during early learning there is an advantage for encoding sequences in sensory frames; however, it remains unclear whether this advantage extends to long-term consolidation. Using the serial RT task, we set out to distinguish the dynamics of learning sequential orders of visual cues from learning sequential responses. On each day, most participants learned a new mapping between a set of symbolic cues and responses made with one of four fingers, after which they were exposed to trial blocks of either randomly ordered cues or deterministic ordered cues (12-item sequence). Participants were randomly assigned to one of four groups (n = 15 per group): Visual sequences (same sequence of visual cues across training days), Response sequences (same order of key presses across training days), Combined (same serial order of cues and responses on all training days), and a Control group (a novel sequence each training day). Across 5 days of training, sequence-specific measures of response speed and accuracy improved faster in the Visual group than any of the other three groups, despite no group differences in explicit awareness of the sequence. The two groups that were exposed to the same visual sequence across days showed a marginal improvement in response binding that was not found in the other groups. These results indicate that there is an advantage, in terms of rate of consolidation across multiple days of training, for learning sequences of actions in a sensory representational space, rather than as motoric representations.

In vivo characterization of the connectivity and subcomponents of the human globus pallidus.

Projections from the substantia nigra and striatum traverse through the pallidum on the way to their targets. To date, in vivo characterization of these pathways remains elusive. Here we used high angular resolution diffusion imaging (N=138) to study the characteristics and structural subcompartments of the human pallidum. Our central result shows that the diffusion orientation distribution functions within the pallidum are asymmetrically oriented in a dorsal to dorsolateral direction, consistent with the orientation of underlying fiber systems. We also observed systematic differences in the diffusion signal between the two pallidal segments. Compared to the outer pallidal segment, the internal segment has more peaks in the diffusion orientation distribution and stronger anisotropy in the primary fiber direction, consistent with known cellular differences between the underlying nuclei. These differences in orientation, complexity, and degree of anisotropy are sufficiently robust to automatically segment the pallidal nuclei using diffusion properties. We characterize these patterns in one data set using diffusion spectrum imaging and replicate in a separate sample of subjects imaged using multi-shell imaging, highlighting the reliability of these diffusion patterns within pallidal nuclei. Thus the gray matter diffusion signal can be useful as an in vivo measure of the collective efferent pathways running through the human pallidum.