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Background Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and risk of Parkinson’s disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurotoxicity induced by alpha-synuclein (αSyn), a key player in PD genetics and pathogenesis. Methods Nigral dopaminergic neuron toxicity induced by local overexpression of aSyn was assessed in mice that have an inactivating mutation of MC1R, overexpress its wild-type transgene, or were treated with MC1R agonists. The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in MC1R-mediated protection against αSyn was characterized in vitro. Furthermore, MC1R expression was determined in human postmortem midbrain from patients with PD and unaffected subjects. Results Targeted expression of αSyn in the nigrostriatal pathway induced exacerbated synuclein pathologies in MC1R mutant mice, which were accompanied by neuroinflammation and altered Nrf2 responses, and reversed by the human MC1R transgene. Two MC1R agonists were neuroprotective against αSyn-induced dopaminergic neurotoxicity. In vitro experiments showed that Nrf2 was a necessary mediator of MC1R effects. Lastly, MC1R was present in dopaminergic neurons in the human substantia nigra and appeared to be reduced at the tissue level in PD patients. Conclusion Our study supports an interaction between MC1R and αSyn that can be mediated by neuronal MC1R possibly through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies for PD.

Background: Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor ( MC1R ) and risk of Parkinson disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurotoxicity induced by alpha-synuclein (αSyn), a key player in PD genetics and pathogenesis. Methods: Nigral dopaminergic neuron toxicity induced by local overexpression of aSyn was assessed in mice that had an inactivating mutation of MC1R , overexpressed its wild-type transgene, or were treated with MC1R agonists. The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in MC1R-mediated protection against αSyn was characterized in vitro . Furthermore, MC1R expression was determined in human postmortem midbrains from patients with PD and unaffected subjects. Results: Targeted expression of αSyn in the nigrostriatal pathway induced exacerbated synuclein pathologies in MC1R mutant mice, which were accompanied by neuroinflammation and altered Nrf2 responses, and reversed by the human MC1R transgene. Two MC1R agonists were neuroprotective against αSyn-induced dopaminergic neurotoxicity. In vitro experiments showed that Nrf2 was a necessary mediator of MC1R effects. Lastly, MC1R was present in dopaminergic neurons in the human substantia nigra and appeared to be reduced in PD patients. Conclusion: Our study supports an interaction between MC1R and αSyn that can be mediated by neuronal MC1R through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies for PD.

Background: Epidemiological, laboratory and clinical studies have established an association between elevated urate and high blood pressure (BP). However, the inference of causality remains controversial. A naturally occurring antioxidant, urate may also be neuroprotective, and urate-elevating treatment with its precursor inosine is currently under clinical development as a potential disease-modifying strategy for Parkinson's disease (PD). Methods: Our study takes advantage of a recently completed phase II trial evaluating oral inosine in de novo non-disabling early PD with no major cardiovascular and nephrological conditions, and of three lines of genetically engineered mice: urate oxidase (UOx) global knockout (gKO), conditional KO (cKO), and transgenic (Tg) mice with markedly elevated, mildly elevated, and substantially reduced serum urate, respectively, to systematically investigate effects of urate-modifying manipulation on BP. Findings: Among clinical trial participants, change in serum urate but not changes in systolic, diastolic and orthostatic BP differed by treatment group. There was no positive correlation between urate elevations and changes in systolic, diastolic and orthostatic BP. Between UOx gKO, cKO, or Tg mice and their respective wild type littermates there were no significant differences in systolic or diastolic BP or in their responses to BP-regulating interventions. Interpretation: Our complementary preclinical and human studies of urate modulation in animal models and in generally healthy early PD do not support a hypertensive effect of urate elevation or an association between urate and BP. Funding: U.S. Department of Defense, RJG Foundation, Michael J. Fox Foundation LEAPS program, National Institutes of Health, American Federation for Aging Research, Parkinson's Disease Foundation Advancing Parkinson's Therapies initiative. Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: The study protocol of PD patients was approved by the institutional review boards of the Administrative Coordination Center at Massachusetts General Hospital (MGH), the Clinical Coordination Center at University of Rochester and all clinical sites, and participants provided written informed consent.

Alpha-synuclein (αSyn) is encoded by the first causal gene identified in Parkinson's disease (PD) and is the main component of Lewy bodies, a pathological hallmark of PD. aSyn-based animal models have contributed to our understanding of PD pathophysiology and to the development of therapeutics. Overexpression of human wildtype αSyn by viral vectors in rodents recapitulates the loss of dopaminergic neurons from the substantia nigra, another defining pathological feature of the disease. The development of a rat model exhibiting bimolecular fluorescence complementation (BiFC) of αSyn by recombinant adeno-associated virus facilitates detection of the toxic αSyn oligomers species. We report here neurochemical, neuropathological and behavioral characterization of BiFC of αSyn in mice. Overexpression and oligomerization of αSyn through BiFC is detected by conjugated fluorescence. Reduced striatal dopamine and loss of nigral dopaminergic neurons are accompanied neuroinflammation and abnormal motor activities. Our mouse model may provide a valuable tool to study the role of αSyn in PD and to explore therapeutic approaches. Keywords: Parkinson's disease, Alpha-synuclein, Mouse model, Oligomers, Neuroinflammation

Several studies have been conducted with mixed results since our initial report of increased Parkinson's disease risk in individuals with red hair and/or red hair‐associated p.R151C variant of the MC1R gene, both of which confer high melanoma risk. We performed a meta‐analysis of six publications on red hair, MC1R, and Parkinson's disease. We found that red hair (pooled odds ratios = 1.68, 95% confidence intervals: 1.07, 2.64) and p.R151C (pooled odds ratios = 1.10, 95% confidence intervals: 1.00, 1.21), but not p.R160W, were associated with greater risk for Parkinson's disease. Our results support potential roles of pigmentation and its key regulator MC1R in the pathogenesis of Parkinson's disease.

Neuronal activity patterns are disrupted in neurodegenerative disorders, including Alzheimer’s disease (AD). One example is disruption of corticothalamic slow oscillations responsible for sleep-dependent memory consolidation. Slow waves are periodic oscillations in neuronal activity occurring at frequencies of

The striatum, the entry nucleus of the basal ganglia, lacks laminar or columnar organization of its principal cells; nevertheless, functional data suggest that it is spatially organized. Here we examine whether the connectivity and synaptic organization of striatal GABAergic interneurons contributes to such spatial organization. Focusing on the two main classes of striatal GABAergic interneurons (fast-spiking interneurons [FSIs] and low-threshold-spiking interneurons [LTSIs]), we apply a combination of optogenetics and viral tracing approaches to dissect striatal microcircuits in mice. Our results reveal fundamental differences between the synaptic organizations of both interneuron types. FSIs target exclusively striatal projection neurons (SPNs) within close proximity and form strong synapses on the proximal somatodendritic region. In contrast, LTSIs target both SPNs and cholinergic interneurons, and synaptic connections onto SPNs are made exclusively over long distances and onto distal dendrites. These results suggest fundamentally different functions of FSIs and LTSIs in shaping striatal output.

We demonstrate that three-photon microscopy (3PM) with 1300-nm excitation enables functional imaging of GCaMP6s labeled neurons beyond the depth limit of two-photon microscopy (2PM) with 920-nm excitation. We quantitatively compared 2PM and 3PM imaging of calcium indicator GCaMP6s by measuring correlation between activity traces, absolute signal level, excitation attenuation with depth, and signal-to-background ratio (SBR). Compared to 2PM imaging of GCaMP6s-labeled neurons, 3PM imaging has increasingly larger advantages in signal strength and SBR as the imaging depth increases in densely labeled mouse brain, given the same pulse energy, pulse width, and repetition rate at the sample surface. For example, 3PM has comparable signal strength as 2PM and up to two orders of magnitude higher SBR as 2PM in mouse cortex around 700-800um. We also demonstrate 3PM activity recording of 150 neurons in the hippocampal stratum pyramidale (SP) at 1mm depth, which is inaccessible to non-invasive 2PM imaging. Our work establishes 3PM as a powerful tool for calcium imaging at the depth beyond 2PM limits.

High-resolution optical imaging is critical to understanding brain function. We demonstrate that three-photon microscopy at 1,300-nm excitation enables functional imaging of GCaMP6s-labeled neurons beyond the depth limit of two-photon microscopy. We record spontaneous activity from up to 150 neurons in the hippocampal stratum pyramidale at ∼1-mm depth within an intact mouse brain. Our method creates opportunities for noninvasive recording of neuronal activity with high spatial and temporal resolution deep within scattering brain tissues.

Slow oscillations are important for consolidation of memory during sleep, and Alzheimer’s disease (AD) patients experience memory disturbances. Thus, we examined slow oscillation activity in an animal model of AD. APP mice exhibit aberrant slow oscillation activity. Aberrant inhibitory activity within the cortical circuit was responsible for slow oscillation dysfunction, since topical application of GABA restored slow oscillations in APP mice. In addition, light activation of channelrhodopsin-2 (ChR2) expressed in excitatory cortical neurons restored slow oscillations by synchronizing neuronal activity. Driving slow oscillation activity with ChR2 halted amyloid plaque deposition and prevented calcium overload associated with this pathology. Thus, targeting slow oscillatory activity in AD patients might prevent neurodegenerative phenotypes and slow disease progression.

Urine release (micturition) serves an essential physiological function as well as a critical role in social communication in many animals. Here, we show a combined effect of olfaction and social hierarchy on micturition patterns in adult male mice, confirming the existence of a micturition control center that integrates pro- and anti-micturition cues. Furthermore, we demonstrate that a cluster of neurons expressing corticotropin-releasing hormone (Crh) in the pontine micturition center (PMC) is electrophysiologically distinct from their Crh-negative neighbors and sends glutamatergic projections to the spinal cord. The activity of PMC Crh-expressing neurons correlates with and is sufficient to drive bladder contraction, and when silenced impairs micturition behavior. These neurons receive convergent input from widespread higher brain areas that are capable of carrying diverse pro- and anti-micturition signals, and whose activity modulates hierarchy-dependent micturition. Taken together, our results indicate that PMC Crh-expressing neurons are likely the integration center for context-dependent micturition behavior.

Epidemiological studies support a general inverse association between the risk of cancer development and Parkinson's disease (PD). In recent years however, increasing amount of eclectic evidence points to a positive association between PD and cancers through different temporal analyses and ethnic groups. This positive association has been supported by several common genetic mutations in SNCA, PARK2, PARK8, ATM, p53, PTEN, and MC1R resulting in cellular changes such as mitochondrial dysfunction, aberrant protein aggregation, and cell cycle dysregulation. Here, we review the epidemiological and biological advances of the past decade in the association between PD and cancers to offer insight on the recent and sometimes contradictory findings.

We demonstrate three-photon microscopy (3PM) at 1300-nm-excitation for imaging neuronal activity through the entire neocortex and as deep as the hippocampal stratum pyramidale (SP) layer of the living adult mouse brain using genetically-encoded calcium indicators.

We demonstrate three-photon microscopy (3PM) at 1300-nm excitation for imaging neuronal activity as deep as layer-6 (L6) of adult mouse cortex using genetically-encoded calcium indicators. In vivo imaging of subcortical, GFP-labeled neurons is also demonstrated.