Pathogenic or protective? Neuropeptide Y in amyotrophic lateral sclerosis.

Neuropeptide Y (NPY) is an endogenous peptide of the central and enteric nervous systems which has gained significant interest as a potential neuroprotective agent for treatment of neurodegenerative disease. Amyotrophic lateral sclerosis (ALS) is an aggressive and fatal neurodegenerative disease characterized by motor deficits and motor neuron loss. In ALS, recent evidence from ALS patients and animal models has indicated that NPY may have a role in the disease pathogenesis. Increased NPY levels were found to correlate with disease progression in ALS patients. Similarly, NPY expression is increased in the motor cortex of ALS mice by end stages of the disease. Although the functional consequence of increased NPY levels in ALS is currently unknown, NPY has been shown to exert a diverse range of neuroprotective roles in other neurodegenerative diseases; through modulation of potassium channel activity, increased production of neurotrophins, inhibition of endoplasmic reticulum stress and autophagy, reduction of excitotoxicity, oxidative stress, neuroinflammation and hyperexcitability. Several of these mechanisms and signalling pathways are heavily implicated in the pathogenesis of ALS. Therefore, in this review, we discuss possible effects of NPY and NPY-receptor signalling in the ALS disease context, as determining NPY's contribution to, or impact on, ALS disease mechanisms will be essential for future studies investigating the NPY system as a therapeutic strategy in this devastating disease.

The Benefits of Participating in a Learning Assistant Program on the Metacognitive Awareness and Motivation of Learning Assistants.

Learning assistant (LA) programs train undergraduate students to foster peer discussion and facilitate active-learning activities in undergraduate science, technology, engineering, and mathematics (STEM) classes. Students who take courses that are supported by LAs demonstrate better conceptual understanding, lower failure rates, and higher satisfaction with the course. There is less work, however, on the impact that participating in LA programs has on the LAs themselves. The current study implements a pretest-posttest design to assess changes in LAs' metacognition and motivation to succeed in STEM across their first and second quarters as an LA. Our findings suggest that participating in this program may help LAs become more reflective learners, as was demonstrated by an increase in their scores on the Metacognitive Awareness Inventory (MAI) after the first quarter. LAs also showed increases on the Intrinsic Motivation and Self-Efficacy subscales of the Science Motivation Questionnaire. Students who participated in the program for an additional quarter continued to show increases in their MAI scores and maintained the gains that were observed in their motivation. Taken together, this work suggests that, in addition to benefiting the learner, LA programs may have positive impacts on the LAs themselves.

Intranasal neuropeptide Y1 receptor antagonism improves motor deficits in symptomatic SOD1 ALS mice.

OBJECTIVE: Neuropeptide Y (NPY) is a 36 amino acid peptide widely considered to provide neuroprotection in a range of neurodegenerative diseases. In the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), recent evidence supports a link between NPY and ALS disease processes. The goal of this study was to determine the therapeutic potential and role of NPY in ALS, harnessing the brain-targeted intranasal delivery of the peptide, previously utilised to correct motor and cognitive phenotypes in other neurological conditions. METHODS: To confirm the association with clinical disease characteristics, NPY expression was quantified in post-mortem motor cortex tissue of ALS patients and age-matched controls. The effect of NPY on ALS cortical pathophysiology was investigated using slice electrophysiology and multi-electrode array recordings of SOD1G93A cortical cultures in vitro. The impact of NPY on ALS disease trajectory was investigated by treating SOD1G93A mice intranasally with NPY and selective NPY receptor agonists and antagonists from pre-symptomatic and symptomatic phases of disease. RESULTS: In the human post-mortem ALS motor cortex, we observe a significant increase in NPY expression, which is not present in the somatosensory cortex. In vitro, we demonstrate that NPY can ameliorate ALS hyperexcitability, while brain-targeted nasal delivery of NPY and a selective NPY Y1 receptor antagonist modified survival and motor deficits specifically within the symptomatic phase of the disease in the ALS SOD1G93A mouse. INTERPRETATION: Taken together, these findings highlight the capacity for non-invasive brain-targeted interventions in ALS and support antagonism of NPY Y1Rs as a novel strategy to improve ALS motor function.

Estrogen Enhances Dendrite Spine Function and Recovers Deficits in Neuroplasticity in the prpTDP-43A315T Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) attacks the corticomotor system, with motor cortex function affected early in disease. Younger females have a lower relative risk of succumbing to ALS than males and older females, implicating a role for female sex hormones in disease progression. However, the mechanisms driving this dimorphic incidence are still largely unknown. We endeavoured to determine if estrogen mitigates disease progression and pathogenesis, focussing upon the dendritic spine as a site of action. Using two-photon live imaging we identify, in the prpTDP-43A315T mouse model of ALS, that dendritic spines in the male motor cortex have a reduced capacity for remodelling than their wild-type controls. In contrast, females show higher capacity for remodelling, with peak plasticity corresponding to highest estrogen levels during the estrous cycle. Estrogen manipulation through ovariectomies and estrogen replacement with 17ß estradiol in vivo was found to significantly alter spine density and mitigate disease severity. Collectively, these findings reveal that synpatic plasticity is reduced in ALS, which can be amelioriated with estrogen, in conjuction with improved disease outcomes.

Improving conceptual learning via pretests.

Although examples can be structured to emphasize diagnostic features of concepts, novice learners tend to focus on irrelevant surface features and struggle to encode deeper structures. Experiment 1 examined whether pretesting-answering questions about content before it is studied-could enhance learners' noticing of diagnostic features, making them easier to process during subsequent study. Participants studied statistical concepts with examples that emphasized surface details or deep structure, and then classified new examples of these concepts. Studying examples that emphasized deep structure increased classification performance compared to examples that emphasized surface details. Moreover, taking pretests prior to studying the examples increased classification performance and eliminated differential benefits of studying structure versus surface examples. Experiment 2 examined whether pretesting serves a role beyond directing attention. After studying different statistical concepts with only surface-emphasizing examples, classification performance was better when participants actually took pretests compared to being given the correct responses. It is the generative aspect of pretesting, beyond attention directing, that improves conceptual learning among novice learners. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Differential NPY-Y1 Receptor Density in the Motor Cortex of ALS Patients and Familial Model of ALS.

Destabilization of faciliatory and inhibitory circuits is an important feature of corticomotor pathology in amyotrophic lateral sclerosis (ALS). While GABAergic inputs to upper motor neurons are reduced in models of the disease, less understood is the involvement of peptidergic inputs to upper motor neurons in ALS. The neuropeptide Y (NPY) system has been shown to confer neuroprotection against numerous pathogenic mechanisms implicated in ALS. However, little is known about how the NPY system functions in the motor system. Herein, we investigate post-synaptic NPY signaling on upper motor neurons in the rodent and human motor cortex, and on cortical neuron populations in vitro. Using immunohistochemistry, we show the increased density of NPY-Y1 receptors on the soma of SMI32-positive upper motor neurons in post-mortem ALS cases and SOD1G93A excitatory cortical neurons in vitro. Analysis of receptor density on Thy1-YFP-H-positive upper motor neurons in wild-type and SOD1G93A mouse tissue revealed that the distribution of NPY-Y1 receptors was changed on the apical processes at early-symptomatic and late-symptomatic disease stages. Together, our data demonstrate the differential density of NPY-Y1 receptors on upper motor neurons in a familial model of ALS and in ALS cases, indicating a novel pathway that may be targeted to modulate upper motor neuron activity.

The evolutionary history of Darwin's finches: speciation, gene flow, and introgression in a fragmented landscape.

Many classic examples of adaptive radiations take place within fragmented systems such as islands or mountains, but the roles of mosaic landscapes and variable gene flow in facilitating species diversification is poorly understood. Here we combine phylogenetic and landscape genetic approaches to understand diversification in Darwin's finches, a model adaptive radiation. We combined sequence data from 14 nuclear introns, mitochondrial markers, and microsatellite variation from 51 populations of all 15 recognized species. Phylogenetic species-trees recovered seven major finch clades: ground, tree, vegetarian, Cocos Island, grey and green warbler finches, and a distinct clade of sharp-beaked ground finches (Geospiza cf. difficilis) basal to all ground and tree finches. The ground and tree finch clades lack species-level phylogenetic structure. Interisland gene flow and interspecies introgression vary geographically in predictable ways. First, several species exhibit concordant patterns of population divergence across the channel separating the Galápagos platform islands from the separate volcanic province of northern islands. Second, peripheral islands have more admixed populations while central islands maintain more distinct species boundaries. This landscape perspective highlights a likely role for isolation of peripheral populations in initial divergence, and demonstrates that peripheral populations may maintain genetic diversity through outbreeding during the initial stages of speciation.