Synucleinopathies including Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal intracellular inclusions of α-synuclein (α-synuclein). Parkinson’s disease dementia (PDD) and DLB are collectively the second most common cause of neurodegenerative dementia. In addition to associated inclusions, Lewy body diseases have dopaminergic neurodegeneration, motor defects and cognitive changes. The microtubule-associated protein tau has been implicated in LBDs, but the exact role of the protein and how it influences formation of α-synuclein inclusions is unknown. Reducing endogenous tau levels is protective in multiple models of Alzheimer’s disease (AD), tauopathies, and in some transgenic synucleinopathy mouse models. Recombinant α-synuclein and tau proteins interact in vitro . Here, we show tau and α-synuclein colocalize at excitatory presynaptic terminals. However, tau heterozygous and tau knockout mice do not show a reduction in fibril-induced α-synuclein inclusions formation...

Protein aggregation can induce explicit neurotoxic events that trigger a number of presently untreatable neurodegenerative disorders. Chaperones, on the other hand, play a neuroprotective role due to their ability to unfold and refold abnormal proteins. Progressive nature of neurotoxic events makes it important to discover endogenous factors that affect pathological and molecular phenotypes of neurodegeneration in animal models. Here, we identified microtubule-associated protein tau, and chaperones Hsp70 (heat shock protein 70) and DNAJA1 (DJ2) as endogenous substrates of cereblon (CRBN), a substrate-recruiting-subunit of cullin4-RING-E3-ligase. This recruitment results in ubiquitin-mediated degradation of tau, Hsp70, and DJ2. Knocking-out CRBN enhances chaperone activity of DJ2, resulting in decreased phosphorylation and aggregation of tau, improved association of tau with microtubules and reduced accumulation of pathological tau across brain. Functionally abundant DJ2 could prevent tau aggregation induce...

Most neuroimaging experiments that investigate how tools and their actions are represented in the brain use visual paradigms where tools or hands are displayed as 2D images and no real movements are performed. These studies discovered selective visual responses in occipito-temporal and parietal cortices for viewing pictures of hands or tools, which are assumed to reflect action processing, but this has rarely been directly investigated. Here, we examined the responses of independently visually defined category-selective brain areas when participants grasped 3D tools (N=20; 9 females). Using real action fMRI and multi-voxel pattern analysis, we found that grasp typicality representations (i.e., whether a tool is grasped appropriately for use) were decodable from hand-selective areas in occipito-temporal and parietal cortices, but not from tool-, object-, or body-selective areas, even if partially overlapping. Importantly, these effects were exclusive for actions with tools, but not for biomechanically match...

Axon regeneration is an evolutionarily conserved process essential for restoring the function of damaged neurons. In Caenorhabditis elegans hermaphrodites, initiation of axon regeneration is regulated by the RhoA GTPase–ROCK (Rho-associated coiled-coil kinase)–regulatory non-muscle myosin light-chain phosphorylation signaling pathway. However, the upstream mechanism that activates the RhoA pathway remains unknown. Here, we show that axon injury activates TLN-1/talin via the cAMP–Epac (exchange protein directly activated by cAMP)–Rap GTPase cascade and that TLN-1 induces multiple downstream events, one of which is integrin inside-out activation, leading to the activation of the RhoA–ROCK signaling pathway. We found that the non-receptor tyrosine kinase Src, a key mediator of integrin signaling, activates the Rho guanine nucleotide exchange factor (GEF) EPHX-1/ephexin by phosphorylating the Tyr-568 residue in the autoinhibitory domain. Our results suggest that the C. elegans integrin signaling network regula...

The lateral habenula (LHb) is a phylogenetically primitive brain structure that plays a key role in learning to inhibit distinct responses to specific stimuli. This structure is activated by primary aversive stimuli, cues predicting an imminent aversive event, unexpected reward omissions, and cues associated with the omission of an expected reward. The most widely described effect of LHb activation is acutely suppressing midbrain dopaminergic signaling. However, recent studies have identified multiple means by which the LHb foster this effect as well as other mechanisms of action. These findings reveal the complex nature of LHb function. The present paper reviews the role of this structure in learning from reward omission experiences. We approach this topic from the perspective of computational models of behavioral change that account for inhibitory learning to frame key findings. Such findings are drawn from recent behavioral neuroscience studies that use novel brain imaging, stimulation, ablation, and re...

Nasal breathing generates a rhythmic signal which entrains cortical network oscillations in widespread brain regions on a cycle-to-cycle time scale. It is unknown, however, how respiration and neuronal network activity interact on a larger time scale: are breathing frequency and typical neuronal oscillation patterns correlated? Is there any directionality or temporal relationship? To address these questions, we recorded field potentials from the posterior parietal cortex of mice together with respiration during REM sleep. In this state, the parietal cortex exhibits prominent theta and gamma oscillations while behavioral activity is minimal, reducing confounding signals. We found that the instantaneous breathing frequency strongly correlates with the instantaneous frequency and amplitude of both theta and gamma oscillations. Cross-correlograms and Granger causality revealed specific directionalities for different rhythms: changes in theta activity precede and Granger-cause changes in breathing frequency, su...

In 1981, I published a paper in the first issue of the Journal of Neuroscience with my postdoctoral mentor, Dr. Richard Bunge. At that time, the long-standing belief that each neuron expressed only one neurotransmitter, known as Dale’s Principle (Dale, 1935), was being hotly debated following a report by French embryologist Nicole Le Douarin showing that neural crest cells destined for one transmitter phenotype could express characteristics of another if transplanted to alternate sites in the developing embryo (LeDouarin, 1980). In the Bunge lab, we were able to more directly test the question of phenotypic plasticity in the controlled environment of the tissue culture dish. Thus, in our paper, we grew autonomic catecholaminergic neurons in culture under conditions which promoted the acquisition of cholinergic traits and showed that cells did not abandon their inherited phenotype in order to adopt a new one but instead were capable of dual transmitter expression. In this Progressions article, I detail the ...

Mutations of the gene encoding the RET tyrosine kinase causes Hirschsprung disease (HSCR) and medullary thyroid carcinoma (MTC). Current consensus holds that HSCR and MTC are induced by inactivating and activating RET mutations, respectively. However, it remains unknown whether activating mutations in the RET gene have adverse effects on ENS development in vivo. We addressed this issue by examining mice engineered to express RET51(C618F), an activating mutation identified in MTC patients. Although Ret51(C618F)/51(C618F) mice displayed hyperganglionosis of the ENS, Ret51(C618F)/- mice exhibited severe intestinal aganglionosis due to premature neuronal differentiation. Reduced levels of GDNF, a RET-activating neurotrophic factor, ameliorated the ENS phenotype of Ret51(C618F)/- mice, demonstrating that GDNF-mediated activation of RET51(C618F) is responsible for severe aganglionic phenotype. The RET51(C618F) allele showed genetic interaction with Ednrb gene, one of modifier genes for HSCR. These data reveal th...

Neuron differentiation includes formation and outgrowth of neurites that differentiate into axons or dendrites. Directed neurite outgrowth is controlled by growth cones that protrude and retract actin-rich structures to sense environmental cues. These cues control local actin filament dynamics, steer growth cones towards attractants and away from repellents and navigate neurites through the developing brain. Rodent hippocampal neurons are widely used to study the mechanisms underlying neuron differentiation. Genetic manipulation of isolated neurons including gene inactivation or reporter gene expression can be achieved by classical transfections methods, but these methods are restricted to neurons cultured for several days, after neurite formation or outgrowth. Instead, electroporation allows gene manipulation prior to seeding. However, reporter gene expression usually takes up to 24 hours and time course of gene inactivation depends on the half live of the targeted mRNA and gene product. Hence, these meth...

Parkinson’s disease (PD) is a progressive neurodegenerative disease that is typically diagnosed late in its progression. There is a need for biomarkers suitable for monitoring the disease progression at earlier stages to guide the development of novel neuroprotective therapies. One potential biomarker, α-synuclein, has been found in both the familial cases of PD, as well as the sporadic cases and is considered a key feature of PD. α-synuclein is naturally present in the retina, and it has been suggested that early symptoms of the visual system may be used as a biomarker for PD. Here, we use a viral vector to induce a unilateral expression of human wildtype α-synuclein in rats as a mechanistic model of protein aggregation in PD. We employed functional magnetic resonance imaging (fMRI) to investigate whether adeno-associated virus (AAV) mediated expression of human wildtype α-synuclein alter functional activity in the visual system. 16 rats were injected with either AAV-α-synuclein (n=7) or AAV-null (n=9) i...