Pupil dynamics alterations have been found in patients affected by a variety of neuropsychiatric conditions, including autism. Studies in mouse models have used pupillometry for phenotypic assessment and as a proxy for arousal. Both in mice and humans, pupillometry is non-invasive and allows for longitudinal experiments supporting temporal specificity, however, its measure requires dedicated setups. Here, we introduce a Convolutional Neural Network that performs online pupillometry in both mice and humans in a web app format. This solution dramatically simplifies the usage of the tool for the non-specialist and non-technical operators. Because a modern web browser is the only software requirement, this choice is of great interest given its easy deployment and set-up time reduction. The tested model performances indicate that the tool is sensitive enough to detect both locomotor-induced and stimulus-evoked pupillary changes, and its output is comparable with state-of-the-art commercial devices. Significanc...

Huntington’s disease (HD) is an inherited neurodegenerative disorder with onset of characteristic motor symptoms at midlife, preceded by subtle cognitive and behavioral disturbances. Transcriptional dysregulation emerges early in the disease course and is considered central to HD pathogenesis. Using wild-type and HD knock-in mouse striatal cell lines we observed a HD genotype-dependent reduction in the protein levels of transcription factor 4 (TCF4), a member of the basic helix-loop-helix family with critical roles in brain development and function. We characterized mouse Tcf4 gene structure and expression of alternative mRNAs and protein isoforms in cell-based models of HD, and in four different brain regions of male transgenic HD mice (R6/1) from young to mature adulthood. The largest decrease in the levels of TCF4 at mRNA and specific protein isoforms were detected in the R6/1 mouse hippocampus. Translating this finding to human disease, we found reduced expression of long TCF4 isoforms in the post-mort...

We report that the neurotrophin receptor p75 contributes to sensory neuron survival through the regulation of cholesterol metabolism in Schwann cells. Selective deletion of p75 in mouse Schwann cells of either sex resulted in a 30% loss of dorsal root ganglia (DRG) neurons and diminished thermal sensitivity. P75 regulates Schwann cell cholesterol biosynthesis in response to BDNF, forming a co-receptor complex with ErbB2 and activating ErbB2-mediated stimulation of SREBP2, a master regulator of cholesterol synthesis. Schwann cells lacking p75 exhibited decreased activation of SREBP2 and a reduction in 7-dehydrocholesterol reductase (DHCR7) expression, resulting in accumulation of the neurotoxic intermediate, 7-dehyrocholesterol in the sciatic nerve. Restoration of DHCR7 in p75 null Schwann cells in mice significantly attenuated DRG neuron loss. Together, these results reveal a mechanism by which the disruption of lipid metabolism in glial cells negatively influences sensory neuron survival, which has implic...

Spontaneous recognition memory tasks are widely used to assess cognitive function in rodents and have become commonplace in the characterization of rodent models of neurodegenerative, neuropsychiatric and neurodevelopmental disorders. Leveraging an animal’s innate preference for novelty, these tasks use object exploration to capture the what, where and when components of recognition memory. Choosing and optimizing objects is a key feature when designing recognition memory tasks. Although the range of objects used in these tasks varies extensively across studies, object features can bias exploration, influence task difficulty and alter brain circuit recruitment. Here, we discuss the advantages of using 3D printed objects in rodent spontaneous recognition memory tasks. We provide strategies for optimizing their design and usage, and offer a repository of tested, open-source designs for use with commonly used rodent species. The easy accessibility, low-cost, renewability and flexibility of 3D printed open-sou...

Neuroendocrine control of reproduction is disrupted in many individuals with polycystic ovary syndrome, who present with increased luteinizing hormone (LH), and presumably gonadotropin-releasing hormone (GnRH), release frequency, and high androgen levels. Prenatal androgenization (PNA) recapitulates these phenotypes in primates and rodents. Female offspring of mice injected with dihydrotestosterone (DHT) on gestational D16-18 exhibit disrupted estrous cyclicity, increased LH and testosterone, and increased GnRH neuron firing rate as adults. PNA also alters the developmental trajectory of GnRH neuron firing rates, markedly blunting the prepubertal peak in firing that occurs in 3wk-old controls. GnRH neurons do not express detectable androgen receptors and are thus probably not the direct target of DHT. Rather, PNA likely alters GnRH neuronal activity by modulating upstream neurons, such as hypothalamic arcuate neurons co-expressing kisspeptin, neurokinin B (gene Tac2), and dynorphin, aka KNDy neurons. We hy...

Cortical parvalbumin (Pvalb)-expressing neurons provide robust inhibition to neighboring pyramidal neurons, crucial for the proper functioning of cortical networks. This class of inhibitory neurons undergoes extensive synaptic formation and maturation during the first weeks after birth and continue to dynamically maintain their synaptic output throughout adulthood. While several transcription factors, such as Nkx2-1, Lhx6, and Sox6, are known to be necessary for the differentiation of progenitors into Pvalb+ neurons, which transcriptional programs underlie the postnatal maturation and maintenance of Pvalb+ neurons’ innervation and synaptic function remains largely unknown. Because Sox6 is continuously expressed in Pvalb+ neurons until adulthood, we utilized conditional knockout strategies to investigate its putative role in the postnatal maturation and synaptic function of cortical Pvalb+ neurons in mice of both sexes. We found that early postnatal loss of Sox6 in Pvalb+ neurons leads to failure of synapti...

In natural conversations, listeners must attend to what others are saying while ignoring extraneous background sounds. Recent studies have used encoding models to predict electroencephalography (EEG) responses to speech in noise-free listening situations, sometimes referred to as “speech tracking”. Researchers have analyzed how speech tracking changes with different types of background noise. It is unclear, however, whether neural responses from acoustically rich, naturalistic environments with and without background noise can be generalized to more controlled stimuli. If encoding models for acoustically rich, naturalistic stimuli are generalizable to other tasks, this could aid in data collection from populations who may not tolerate listening to more controlled and less-engaging stimuli for long periods of time. We recorded non-invasive scalp EEG while 17 human (8 male/9 female) participants listened to speech without noise and audiovisual speech stimuli containing overlapping speakers and background sou...

Most human movements require coordinated activation of multiple muscles. Although many studies reported associations between arm, leg, and trunk muscles during functional tasks, their neural interaction mechanisms still remain unclear. Therefore, the aim of our study was to investigate arm-trunk or arm-leg neural interactions in the corticospinal tract during different arm muscle contractions. Specifically, we examined corticospinal excitability of the erector spinae (ES; trunk extensor), rectus abdominis (RA; trunk flexor), and tibialis anterior (TA; leg) muscles while participants exerted: (1) wrist flexion; and (2) wrist extension isometric contraction at various contraction intensity levels ranging from rest to 50% of maximal voluntary contraction (MVC) effort. Corticospinal excitability was assessed using motor evoked potentials (MEPs) elicited through motor cortex transcranial magnetic stimulation. Results showed that ES MEPs were facilitated even at low contractions (>5% MVC) during wrist flexion an...

Previous studies have shown that self-generated stimuli in auditory, visual, and somatosensory domains are attenuated, producing decreased behavioral and neural responses compared to the same stimuli that are externally generated. Yet, whether such attenuation also occurs for higher-level cognitive functions beyond sensorimotor processing remains unknown. In this study, we assessed whether cognitive functions such as numerosity estimations are subject to attenuation in 56 healthy participants (32 women). We designed a task allowing the controlled comparison of numerosity estimations for self (active condition) and externally (passive condition) generated words. Our behavioral results showed a larger underestimation of self- compared to externally-generated words, suggesting that numerosity estimations for self-generated words are attenuated. Moreover, the linear relationship between the reported and actual number of words was stronger for self-generated words, although the ability to track errors about num...

Alzheimer's disease is associated with poor sleep, but the impact of tau and β-amyloid (Aβ) pathology on sleep remains largely unknown. Here, we test the hypothesis that tau and Aβ predict unique impairments in objective and self-perceived human sleep under real-life, free-living conditions. Eighty-nine male and female cognitively healthy older adults received 18F-FTP-tau and 11C-PIB-Aβ PET imaging, 7 nights of sleep actigraphy and questionnaire measures, and neurocognitive assessment. Tau burden, but not Aβ, was associated with markedly worse objective sleep. In contrast, Aβ and tau were associated with worse self-reported sleep quality. Of clinical relevance, Aβ burden predicted a unique perceptual mismatch between objective and subject sleep evaluation, with individuals underestimating their sleep. The magnitude of this mismatch was further predicted by worse executive function. Thus, early-stage tau and Aβ deposition are linked with distinct phenotypes of real-world sleep impairment, one that includes ...