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The primary motor cortex (MOp) is an important site for motor skill learning. Interestingly, neurons in MOp possess reward-related activity, presumably to facilitate reward-based motor learning. While pyramidal neurons (PNs) and different subtypes of GABAergic inhibitory interneurons (INs) in MOp all undergo cell-type specific plastic changes during motor learning, the vasoactive intestinal peptide-expressing inhibitory interneurons (VIP-INs) in MOp have been shown to preferentially respond to reward and play a critical role in the early phases of motor learning by triggering local circuit plasticity. To understand how VIP-INs might integrate various streams of information, such as sensory, pre-motor, and reward-related inputs, to regulate local plasticity in MOp, we performed monosynaptic rabies tracing experiments and employed an automated cell counting pipeline to generate a comprehensive map of brain-wide inputs to VIP-INs in MOp. We then compared this input profile to the brain-wide inputs to somatostatin-expressing inhibitory interneurons (SST-INs) and parvalbumin-expressing inhibitory interneurons (PV-INs) in MOp. We found that while all cell types received major inputs from sensory, motor, and prefrontal cortical regions, as well as from various thalamic nuclei, VIP-INs received more inputs from the orbital frontal cortex (ORB) - a region associated with reinforcement learning and value predictions. Our findings provide insight on how the brain leverages microcircuit motifs by both integrating and partitioning different streams of long-range input to modulate local circuit activity and plasticity.

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During motor learning, dendritic spines on pyramidal neurons (PNs) in the primary motor cortex (M1) undergo reorganization. Intriguingly, the inhibition from local somatostatin-expressing inhibitory neurons (SST-INs) plays an important role in regulating the PN plasticity and thus new motor skill acquisition. However, the molecular mechanisms underlying this process remain unclear. Here, we identified that the early-response transcription factor, NPAS4, is selectively expressed in SST-INs during motor learning. By utilizing in vivo two-photon imaging in mice, we found that cell-type-specific deletion of Npas4 in M1 disrupted learning-induced spine reorganization among PNs and impaired motor learning. In addition, NPAS4-expressing SST-INs exhibited lower neuronal activity during task-related movements, and chemogenetically increasing the activity of NPAS4-expressing ensembles was sufficient to mimic the effects of Npas4 deletion. Together, our results reveal an instructive role of NPAS4-expressing SST-INs in modulating the inhibition to downstream task-related PNs to allow proper spine reorganization that is critical for motor learning.

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Children with autism spectrum disorder often exhibit delays in achieving motor developmental milestones such as crawling, walking and speech articulation. However, little is known about the neural mechanisms underlying motor-related deficits. Here, we reveal that mice with a syntenic deletion of the chromosome 16p11.2, a common copy number variation associated with autism spectrum disorder, also exhibit delayed motor learning without showing gross motor deficits. Using in vivo two-photon imaging in awake mice, we find that layer 2/3 excitatory neurons in the motor cortex of adult male 16p11.2-deletion mice show abnormally high activity during the initial phase of learning, and the process of learning-induced spine reorganization is prolonged. Pharmacogenetic activation of locus coeruleus noradrenergic neurons was sufficient to rescue the circuit deficits and the delayed motor learning in these mice. Our results unveil an unanticipated role of noradrenergic neuromodulation in improving the delayed motor learning in 16p11.2-deletion male mice.

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The exquisite intricacies of neural circuits are fundamental to an animal's diverse and complex repertoire of sensory and motor functions. The ability to precisely map neural circuits and to selectively manipulate neural activity is critical to understanding brain function and has, therefore been a long-standing goal for neuroscientists. The recent development of optogenetic tools, combined with transgenic mouse lines, has endowed us with unprecedented spatiotemporal precision in circuit analysis. These advances greatly expand the scope of tractable experimental investigations. Here, in the first half of the review, we will present applications of optogenetics in identifying connectivity between different local neuronal cell types and of long-range projections with both in vitro and in vivo methods. We will then discuss how these tools can be used to reveal the functional roles of these cell-type specific connections in governing sensory information processing, and learning and memory in the visual cortex, somatosensory cortex, and motor cortex. Finally, we will discuss the prospect of new optogenetic tools and how their application can further advance modern neuroscience. In summary, this review serves as a primer to exemplify how optogenetics can be used in sophisticated modern circuit analyses at the levels of synapses, cells, network connectivity and behaviors.

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Motor skill learning induces long-lasting reorganization of dendritic spines, principal sites of excitatory synapses, in the motor cortex. However, mechanisms that regulate these excitatory synaptic changes remain poorly understood. Here, using in vivo two-photon imaging in awake mice, we found that learning-induced spine reorganization of layer (L) 2/3 excitatory neurons occurs in the distal branches of their apical dendrites in L1 but not in the perisomatic dendrites. This compartment-specific spine reorganization coincided with subtype-specific plasticity of local inhibitory circuits. Somatostatin-expressing inhibitory neurons (SOM-INs), which mainly inhibit distal dendrites of excitatory neurons, showed a decrease in axonal boutons immediately after the training began, whereas parvalbumin-expressing inhibitory neurons (PV-INs), which mainly inhibit perisomatic regions of excitatory neurons, exhibited a gradual increase in axonal boutons during training. Optogenetic enhancement and suppression of SOM-IN activity during training destabilized and hyperstabilized spines, respectively, and both manipulations impaired the learning of stereotyped movements. Our results identify SOM inhibition of distal dendrites as a key regulator of learning-related changes in excitatory synapses and the acquisition of motor skills.

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The motor cortex is capable of reliably driving complex movements yet exhibits considerable plasticity during motor learning. These observations suggest that the fundamental relationship between motor cortex activity and movement may not be fixed but is instead shaped by learning; however, to what extent and how motor learning shapes this relationship are not fully understood. Here we addressed this issue by using in vivo two-photon calcium imaging to monitor the activity of the same population of hundreds of layer 2/3 neurons while mice learned a forelimb lever-press task over two weeks. Excitatory and inhibitory neurons were identified by transgenic labelling. Inhibitory neuron activity was relatively stable and balanced local excitatory neuron activity on a movement-by-movement basis, whereas excitatory neuron activity showed higher dynamism during the initial phase of learning. The dynamics of excitatory neurons during the initial phase involved the expansion of the movement-related population which explored various activity patterns even during similar movements. This was followed by a refinement into a smaller population exhibiting reproducible spatiotemporal sequences of activity. This pattern of activity associated with the learned movement was unique to expert animals and not observed during similar movements made during the naive phase, and the relationship between neuronal activity and individual movements became more consistent with learning. These changes in population activity coincided with a transient increase in dendritic spine turnover in these neurons. Our results indicate that a novel and reproducible activity-movement relationship develops as a result of motor learning, and we speculate that synaptic plasticity within the motor cortex underlies the emergence of reproducible spatiotemporal activity patterns for learned movements. These results underscore the profound influence of learning on the way that the cortex produces movements.

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PURPOSE: To evaluate the efficacy and safety of long-term application of autologous serum eye drops treating recalcitrant dry eye syndrome. METHODS: A retrospective chart review was conducted of patients who had serum eye drops between May 2001 and March 2006. The clinical data collected included sex, age, indications for serum eye drops, frequency of lubricant eye drops use before and after serum eye drop treatment, Schirmer tear function test with anaesthesia, fluorescein staining at baseline and at follow up and changes in subjective symptoms. RESULTS: There were 46 eyes of 23 patients (19 female and 4 male) in the study group. The average follow-up period was 17.3 months (range 6-55 months). Corneal fluorescein staining of 34 eyes (73.9%) showed improvement at follow up. Sixteen patients (32 eyes, 69.6%) reported a decreased frequency of lubricant use including eight patients (16 eyes, 34.8%) who used only serum eye drops for dry eye treatment. Eighteen patients (35 eyes, 76.1%) reported subjective improvement after using serum eye drops. No significant complications were reported in this study. CONCLUSION: Serum eye drops can be effective in treating recalcitrant dry eye syndrome and should be available as a management option when other treatments have failed. Meticulous attention must be paid to the possible contamination of the bottle to minimize the risk of infection.

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PURPOSE: To evaluate the long-term safety and efficacy of a new technique using a modified cow-hitch knot for transscleral suture fixation of posterior chamber intraocular lenses (PC IOLs). SETTING: Public hospital in Brisbane, Australia. METHODS: A retrospective chart review was conducted of consecutive patients who had transscleral sutured PC IOL implantation from March 2000 to June 2006 using the new technique, which was modified to eliminate free suture ends and minimize the risk for knot slippage. Data collected included demographic data, ocular history, preoperative and final best corrected visual acuities (BCVAs), preoperative and postoperative intraocular pressure (IOP), and postoperative complications. RESULTS: Eighty-two eyes of 79 patients (51 men, 28 women) with a mean age of 62.5 years+/-18.9 (SD) were included in the study. The mean follow-up was 22.9+/-21.2 months (range 5 to 76 months). The BCVA was 20/40 or better in 45 eyes (54.9%) and 20/200 or worse in 10 eyes (12.2%). The final BCVA was largely determined by the preoperative underlying ocular pathology. Postoperative complications included temporary increased IOP in 14 eyes (17.1%), escalated glaucoma in 7 eyes (8.5%), temporary hypotony in 7 eyes (8.5%), and retinal detachment, hyphema, and irregular astigmatism in 1 eye (1.2%) each. The PC IOLs remained well centered and without tilt in all eyes. CONCLUSIONS: The technique provided excellent PC IOL centration in the presence of no adequate capsule support. It was effective and safe for transscleral suturing of PC IOLs.

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PURPOSE: To report the first case of intraoperative breakage of a microcannula during 25-gauge transconjunctival sutureless vitrectomy. METHOD: Case report. CONCLUSION: Surgeons should be aware of the potential complications of broken microcannulae during 25-gauge transconjunctival sutureless vitrectomy and react promptly to prevent further complications.

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PURPOSE: To evaluate long-term efficacy and safety of the SmartPlug in the management of severe dry eye syndrome. METHODS: A retrospective chart review was conducted of patients who underwent SmartPlug insertion from June 2003 to December 2005. The clinical data collected included sex and age of the patients, indications for plug insertion, Schirmer tear function test with anesthesia, frequency of lubricant eye drop use before and after plug insertion, fluorescein staining at baseline and at last follow-up, and complications. RESULTS: There were 91 eyes of 54 patients (44 women and 10 men) in the study group. The average follow-up period was 13.0 +/- 6.0 months, with a minimum of 6 months. Thirty patients (55 eyes, 60.4%) reported a decreased use of lubricant eye drops after SmartPlug insertion, including 9 patients (14 eyes, 15.4%) who were free of supplementary lubricant eye drops. Forty-one patients (69 eyes, 75.8%) reported subjective symptom improvement after SmartPlug insertion. The corneal fluorescein staining showed overall reduction. Complications included canaliculitis (6 eyes, 6.6%), epiphora requiring plug removal (5 eyes, 5.5%), and spontaneous plug loss (2 eyes, 2.2%). CONCLUSIONS: SmartPlug can be effective in the management of severe dry eye syndrome. However, long-term follow-up is needed for potentially serious complications such as canaliculitis.

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