Brain-derived neurotrophic factor (BDNF) signaling through its receptor, TrkB, modulates survival, differentiation, and synaptic activity of neurons. Both full-length TrkB (TrkB-FL) and its isoform T1 (TrkB.T1) receptors are expressed in neurons; however, whether they follow the same endocytic pathway after BDNF treatment is not known. In this study we report that TrkB-FL and TrkB.T1 receptors traverse divergent endocytic pathways after binding to BDNF. We provide evidence that in neurons TrkB.T1 receptors predominantly recycle back to the cell surface by a "default" mechanism. However, endocytosed TrkB-FL receptors recycle to a lesser extent in a hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-dependent manner which relies on its tyrosine kinase activity. The distinct role of Hrs in promoting recycling of internalized TrkB-FL receptors is independent of its ubiquitin-interacting motif. Moreover, Hrs-sensitive TrkB-FL recycling plays a role in BDNF-induced prolonged mitogen-activated protein kinase (MAPK) activation. These observations provide evidence for differential postendocytic sorting of TrkB-FL and TrkB.T1 receptors to alternate intracellular pathways.

Saccades and smooth pursuit eye movements (SPEM) are two types of goal-directed eye movements whose kinematics differ profoundly, a fact that may have contributed to the notion that the underlying cerebellar substrates are separated. However, it is suggested that some Purkinje cells (PCs) in the oculomotor vermis (OMV) of monkey cerebellum may be involved in both saccades and SPEM, a puzzling finding in view of the different kinematic demands of the two types of eye movements. Such ‘dual’ OMV PCs might be oddities with little if any functional relevance. On the other hand, they might be representatives of a generic mechanism serving as common ground for saccades and SPEM. In our present study, we found that both saccade- and SPEM-related responses of individual PCs could be predicted well by linear combinations of eye acceleration, velocity and position. The relative weights of the contributions that these three kinematic parameters made depended on the type of eye movement. Whereas in the case of saccades eye position was the most important independent variable, it was velocity in the case of SPEM. This dissociation is in accordance with standard models of saccades and SPEM control which emphasize eye position and velocity respectively as the relevant controlled state variables.

J. Neurochem. (2011) 117, 121–132. Abstract Cerebral dopamine neurotrophic factor (CDNF) is a novel evolutionary conserved protein which can protect and restore the function of dopaminergic neurons in the rat model of Parkinson’s disease, suggesting that CDNF might be beneficial for the treatment of Parkinson’s disease. CDNF is widely expressed in neurons in several brain regions including cerebral cortex, hippocampus, substantia nigra, striatum and cerebellum. Human CDNF is glycosylated and secreted from transiently transfected cells; however, the mechanism underlying CDNF secretion is currently unclear. In this study, we found that CDNF could be secreted primarily via the regulated secretion pathway in PC12 cells. The glycosylation of CDNF is not required for its secretion. Moreover, we identified two key subdomains in CDNF which are important for its intracellular localization and secretion. Disrupting helix‐1 of CDNF significantly reduces its constitutive and regulated secretion and the helix‐1 mutant is retained in the endoplasmic reticulum. Although helix‐7 mutation only decreases CDNF regulated secretion and has no effect on its constitutive secretion, which is further supported by the reduction in co‐localization of helix‐7 mutant with secretory granules. In all, these findings will advance our understanding of the molecular mechanism of CDNF trafficking and secretion.

J. Neurochem. (2010) 114, 110–121. Abstract Tropomyosin‐related kinase (Trk) B is a receptor tyrosine kinase for brain‐derived neurotrophic factor (BDNF) which plays a critical role in neuronal survival, differentiation and morphogenesis. Ran‐binding protein in the microtubule‐organizing center (RanBPM) is a cytosolic scaffold protein that has been shown to interact with protein‐tyrosine kinase receptor MET, Axl/Sky, and TrkA in addition to the pan‐neurotrophin receptor pan‐neurotrophin receptor 75 kDa. In this study, we report RanBPM is a novel TrkB‐interacting protein that contributes to BDNF‐induced MAPK and Akt activation together with neuronal morphogenesis and survival. Over‐expression of RanBPM in PC1210 cells (PC12 cells stably over‐expressing TrkB) can significantly enhance BDNF‐induced MAPK and Akt activation. Moreover, RanBPM can promote BDNF‐induced hippocampal neuronal morphogenesis and enhance BDNF‐mediated trophic effects after serum deprivation, while siRNA knock down of RanBPM in cells has the opposite effects. Together, these results suggest that RanBPM may modulate TrkB‐mediated downstream signaling and biological functions.

Recent studies have suggested that microsaccades, the small amplitude saccades made during fixation, are precisely controlled. Two lines of evidence suggest that the cerebellum plays a key role not only in improving the accuracy of macrosaccades but also of microsaccades. First, lesions of the fastigial oculomotor regions (FOR) cause horizontal dysmetria of both micro-and macrosaccades. Secondly, our previous work on Purkinje cell simple spikes in the oculomotor vermis (OV) has established qualitatively similar response preferences for these two groups of saccades. In this work, we investigated the control signals for microand macrosaccades in the FOR, the target of OV Purkinje cell axons. We found that the same FOR neurons discharged for micro-and macrosaccades. For both groups of saccades, FOR neurons exhibited very similar dependencies of their discharge strength on direction and amplitude and very similar burst onset time differences for ipsi-and contraversive saccades and, in both, response duration reflected saccade duration, at least at the population level. An intriguing characteristic of microsaccaderelated responses is that immediate pre-saccadic firing rates decreased with distance to the target center, a pattern that strikingly parallels the eye position dependency of both microsaccade metrics and frequency, which may suggest a potential neural mechanism underlying the role of FOR in fixation. Irrespective of this specific consideration, our study supports the view that microsaccades and macrosaccades share the same cerebellar circuitry and, in general, further strengthens the notion of a microsaccade-macrosaccade continuum.

Similar to memory formation, memory extinction is also a new learning process that requires synaptic plasticity. Actin rearrangement is fundamental for synaptic plasticity, however, whether actin rearrangement in the infralimbic cortex (IL) plays a role in memory extinction, as well as the mechanisms underlying it, remains unclear. Here, using a conditioned taste aversion (CTA) paradigm, we demonstrated increased synaptic density and actin rearrangement in the IL during the extinction of CTA. Targeted infusion of an actin rearrangement inhibitor, cytochalasin D, into the IL impaired memory extinction and de novo synapse formation. Notably, we also found increased myosin II phosphorylation in the IL during the extinction of CTA. Microinfusion of a specific inhibitor of the myosin II ATPase, blebbistatin (Blebb), into the IL impaired memory extinction as well as the related actin rearrangement and changes in synaptic density. Moreover, the extinction deficit and the reduction of synaptic density induced by Blebb could be rescued by the actin polymerization stabilizer jasplakinolide (Jasp), suggesting that myosin II acts via actin filament polymerization to stabilize synaptic plasticity during the extinction of CTA. Taken together, we conclude that myosin II may regulate the plasticity of actin-related synaptic structure during memory extinction. Our studies provide a molecular mechanism for understanding the plasticity of actin rearrangement-associated synaptic structure during memory extinction.

Effects of optogenetic stimulation of primary somatosensory cortex and its projections to striatum on vibrotactile perception in freely moving rats

Smith et al. in Nature Communications, 12, 5121, (2021) provided evidence to challenge the simple dichotomy that learning of actions and expression of habitual behaviors are processed separately in dorsomedial (DMS) and dorsolateral striatum (DLS) by demonstrating that D2 receptor-expressing medium spiny neurons (D2-MSNs) in anterior DLS could modulate newly learned action, except for its involvement in the expression of habitual actions. Here we review recent advances and introduce a valuable addition to the traditional hypothesis by taking into account the common ligand of D1 and D2 neurons, dopamine. Keywords Behavior systems • Operant conditioning • HabitIt has long been proposed that learning of actions and expression of habitual behaviors are processed separately in dorsomedial (DMS) and dorsolateral striatum (DLS), respectively. Within this conceptual framework, it is further hypothesized that activity in the direct pathway could play a role in initiating actions while activation of the striatal indirect pathway might be responsible for the termination of movements. However, recent studies challenge this simple dichotomy by demonstrating that DMS and DLS coordinate with each other and that heterogeneous activities simultaneously exist in direct and indirect pathways.