When discussing procedural learning, it is now routine to consider both online and offline influences for skill acquisition. This is because it is commonly assumed that the evolution of a novel skill memory continues well after practice is over. Indeed, factors impacting offline contributions to skill memory development such as sleep and exercise have garnered considerable research interest in recent years. This is partly due to their capacity to foster post-practice consolidation, a process that has been identified as critical to moving a skill memory from a labile to more stable or elaborate form. While uncovering the potency of non-practice factors to facilitate consolidation is undoubtedly important, the present opinion is designed to remind the reader that a practice schedule, organized to challenge the learner, can, in and of itself, be effective in supporting consolidation resulting in significant gains in long-term skill retention. Significance Statement Adopting “best practices” is an objective...

Savings have been described as the ability of healthy humans to relearn a previously acquired motor skill faster than the first time, which in the context of motor adaptation suggests that the learning rate in the brain could be adjusted when a perturbation is recognized. Alternatively, it has been argued that apparent savings were the consequence of a distinct process that instead of reflecting a change in the learning rate, revealed an explicit re-aiming strategy. Based on recent evidence that feedback adaptation may be central to both planning and control, we hypothesized that this component could genuinely accelerate relearning in human adaptation to force fields during reaching. Consistent with our hypothesis, we observed that upon re-exposure to a previously learned force field, the very first movement performed by healthy volunteers in the relearning context was better adapted to the external disturbance, and this occurred without any anticipation or cognitive strategy because the relearning session...

Galanin, one of the most inducible neuropeptides, is widely present in developing brains, and its expression is altered by pathological events (such as epilepsy, ischemia and axotomy). The roles of galanin in brain development under both normal and pathological conditions have been hypothesized, but the question of how galanin is involved in fetal and early postnatal brain development remains largely unanswered. In this study, using granule cell migration in the cerebellum of early postnatal mice (both sexes) as a model system, we examined the role of galanin in neuronal cell migration during normal development and after brain injury. Here we show that during normal development, endogenous galanin participates in accelerating granule cell migration via altering the Ca2+ and cAMP signaling pathways. Upon brain injury induced by the application of cold insults, galanin levels decrease at the lesion sites, but increase in the surroundings of lesion sites. Granule cells exhibit corresponding changes in migrati...

Recent large genome-wide association studies (GWAS) have identified multiple confident risk loci linked to addiction-associated behavioral traits. Most genetic variants linked to addiction-associated traits lie in non-coding regions of the genome, likely disrupting cis-regulatory element (CRE) function. CREs tend to be highly cell type-specific and may contribute to the functional development of the neural circuits underlying addiction. Yet, a systematic approach for predicting the impact of risk variants on the CREs of specific cell populations is lacking. To dissect the cell types and brain regions underlying addiction-associated traits, we applied stratified LD score regression to compare GWAS to genomic regions collected from human and mouse assays for open chromatin, which is associated with CRE activity. We found enrichment of addiction-associated variants in putative CREs marked by open chromatin in neuronal (NeuN+) nuclei collected from multiple prefrontal cortical areas and striatal regions known ...

Exposure to loud noises not only leads to trauma and loss of output from the ear, but also alters downstream central auditory circuits. A perceptual consequence of noise-induced central auditory disruption is impairment in gap-induced prepulse inhibition, also known as gap detection. Recent studies have implicated cortical parvalbumin-positive (PV) inhibitory interneurons in gap detection and prepulse inhibition. Here we show that exposure to loud noises specifically reduces the density of cortical PV but not somatostatin-positive (SOM) interneurons in the primary auditory cortex (AI) in mice (C57BL/6) of both sexes. Optogenetic activation of PV neurons produced less cortical inhibition in noise-exposed than sham-exposed animals, indicative of reduced PV neuron function. Activation of SOM neurons resulted in similar levels of cortical inhibition in noise- and sham-exposed groups. Furthermore, chemogenetic activation of PV neurons with the hM3-based DREADD (designer receptor exclusively activated by designe...

Temperature-sensitive two-pore domain potassium channels (thermal K2P) are recently shown to cluster at nodes of Ranvier (NRs) and play a key role in action potential (AP) regeneration and conduction on Aβ-afferent nerves. Cooling temperatures affect AP regeneration and conduction on Aβ-afferent nerves but the underlying mechanisms are not completely understood. Here we have performed patch-clamp recordings directly at the NR in an ex vivo trigeminal nerve preparation. We have characterized the effects of cooling temperatures on intrinsic electrophysiological properties and AP regeneration at the NR on rat Aβ-afferent nerves, and determined whether and how thermal K2P channels may be involved in the effects of cooling temperatures. We show that cooling temperatures from 35°C to 15°C decrease outward leak currents, increase input resistance, depolarize resting membrane potential, broaden AP width and increase latency of AP threshold at the NR. We further demonstrate that cooling temperatures impair regenera...

Treatment options for cerebral infarction beyond the time window of reperfusion therapy are limited, and novel approaches are needed. PDGF-B is considered neuroprotective; however, it is difficult to administer at effective concentrations to infarct areas. Nanoparticles (NPs) are small and stable; therefore, we modified PDGF-B to the surface of naturally occurring heat shock protein NPs (HSPNPs) to examine its therapeutic effect in cerebral infarction. PDGF-B modified HSPNPs (PDGF-B HSPNPs) were injected 1 day after transient middle cerebral artery occlusion in CB-17 model mice. We analyzed the infarct volume and motor functional recovery at 3 and 7 days. PDGF-B HSPNPs were specifically distributed in the infarct area, and compared to HSPNPs alone, they significantly reduced infarct volumes and improved neurological function 3 and 7 days after administration. PDGF-B HSPNP administration was associated with strong phosphorylation of Akt in infarct areas and significantly increased neurotrophin-3 production ...

Previous studies have shown that infiltration of capsaicin into the surgical site can prevent incision-induced spontaneous pain like behaviors and heat hyperalgesia. In the present study, we aimed to monitor primary sensory neuron Ca2+ activity in the intact dorsal root ganglia (DRG) using Pirt-GCaMP3 male and female mice pretreated with capsaicin or vehicle prior to the plantar incision. Intraplantar injection of capsaicin (0.05%) significantly attenuated spontaneous pain, mechanical, and heat hypersensitivity after plantar incision. The Ca2+ response in in vivo DRG and in in situ spinal cord was significantly enhanced in the ipsilateral side compared to contralateral side or naïve control. Primary sensory nerve fiber length was significantly decreased in the incision skin area in capsaicin-pretreated animals detected by immunohistochemistry and placental alkaline phosphatase (PLAP) staining. Thus, capsaicin pretreatment attenuates incisional pain by suppressing Ca2+ response due to degeneration of primar...

Different peripheral nerve injuries cause neuropathic pain through distinct mechanisms. Even the site of injury may impact underlying mechanisms as indicated by the clinical finding that the anti-seizure drug carbamazepine (CBZ) relieves pain due to compression injuries of trigeminal but not somatic nerves. We leveraged this observation in the present study hypothesizing that because CBZ blocks voltage-gated sodium channels (VGSCs), its therapeutic selectivity reflects differences between trigeminal and somatic nerves with respect to injury-induced changes in VGSCs. CBZ diminished ongoing and evoked pain behavior in rats with chronic constriction injury (CCI) to the infraorbital nerve (ION) but had minimal effect in rats with sciatic nerve CCI. This difference in behavior was associated with a selective increase in the potency of CBZ-induced inhibition of compound action potentials (CAPs) in the ION, an effect mirrored in human trigeminal versus somatic nerves. The increase in potency was associated with a...

In the spinal cord, classes of interneurons have been studied in vitro to determine their role in producing or regulating locomotion. It is unclear whether all locomotor behaviors are produced by the same circuitry or engage different subsets of neurons. Here, in neonatal mice of either sex, we test this idea by comparing the actions of a class of spinal, inhibitory interneuron (V1) expressing channelrhodopsin driven by the engrailed-1 transcription factor on the rhythms elicited by different methods. We find that even though the overall locomotor activities in vitro are similar, V1 interneuron depolarization produces opposite effects depending of the mode of activation of the locomotor circuitry. The differential behavior of V1 neurons suggests that their function depends on how the locomotor rhythm is activated and is consistent with the idea that the functional organization of the corresponding locomotor networks also differs. SIGNIFICANCE STATEMENT : The neural networks dictating the execution of fi...