The ability to measure changes in neuronal activity in a quantifiable and precise manner is of fundamental importance to understand neuron development and function. Repeated monitoring of neuronal activity of the same population of neurons over several days is challenging and, typically, low-throughput. Here, we describe a new biochemical reporter assay that allows for repeated measurements of neuronal activity in a cell type-specific manner. We coupled activity-dependent elements from the Arc/Arg3.1 gene with a secreted reporter, Gaussia luciferase (Gluc), to quantify neuronal activity without sacrificing the neurons. The reporter predominantly senses calcium and NMDA receptor (NMDAR)-dependent activity. By repeatedly measuring the accumulation of the reporter in cell media, we can profile the developmental dynamics of neuronal activity in cultured neurons from male and female mice. The assay also allows for longitudinal analysis of pharmacological treatments, thus distinguishing acute from delayed respon...

The hedgehog signaling pathway is best known for its role in developmental patterning of the neural tube and limb bud. More recently, hedgehog signaling has been recognized for its roles in growth of adult tissues and maintenance of progenitor cell niches. However, the role of hedgehog signaling in fully differentiated cells like neurons in the adult brain is less clear. In mammals, coordination of hedgehog pathway activity relies on primary cilia and patients with ciliopathies such as Bardet–Biedl and Alström syndrome exhibit clinical features clearly attributable to errant hedgehog such as polydactyly. However, these ciliopathies also present with features not clearly associated with hedgehog signaling such as hyperphagia-associated obesity. How hedgehog signaling may contribute to feeding behavior is complex and unclear, but cilia are critical for proper energy homeostasis. Here, we provide a detailed analysis of the expression of core components of the hedgehog signaling pathway in the adult mouse hypo...

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 (TMS). Results showed that ES MEPs were facilitated even at low contractions (>5% MVC) during wrist flexi...

Neuroendocrine control of reproduction is disrupted in many individuals with polycystic ovary syndrome (PCOS), 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 days 16–18 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 three-week (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,...

Autism spectrum disorders (ASDs) are characterized by abnormal behavioral traits arising from neural circuit dysfunction. While a number of genes have been implicated in ASDs, in most cases, a clear understanding of how mutations in these genes lead to circuit dysfunction and behavioral abnormality is absent. The autism susceptibility candidate 2 ( AUTS2 ) gene is one such gene, associated with ASDs, intellectual disability and a range of other neurodevelopmental conditions. However, the role of AUTS2 in neural development and circuit function is not at all known. Here, we undertook functional analysis of Auts2a, the main homolog of AUTS2 in zebrafish, in the context of the escape behavior. Escape behavior in wild-type zebrafish is critical for survival and is therefore, reliable, rapid, and has well-defined kinematic properties. auts2a mutant zebrafish are viable, have normal gross morphology and can generate escape behavior with normal kinematics. However, the behavior is unreliable and delayed, with hig...

Detection of an unexpected, novel, or salient stimulus typically leads to an orienting response by which animals move the head, in concert with the sensors (e.g., eyes, pinna, whiskers), to evaluate the stimulus. The basal ganglia are known to control orienting movements through tonically active GABAergic neurons in the substantia nigra pars reticulata (SNr) that project to the superior colliculus. Using optogenetics, we explored the ability of GABAergic SNr neurons on one side of the brain to generate orienting movements. In a strain of mice that express channelrhodopsin (ChR2) in both SNr GABAergic neurons and afferent fibers, we found that continuous blue light produced a robust sustained excitation of SNr neurons which generated ipsiversive orienting. Conversely, in the same animal, trains of blue light excited afferent fibers more effectively than continuous blue light, producing a robust sustained inhibition of SNr neurons which generated contraversive orienting. When ChR2 expression was restricted t...

Results from item-method directed forgetting suggest that individuals are able to intentionally forget processed information. Most research suggests that either selective rehearsal of to-be-remembered or inhibitory control of to-be-forgotten information is accountable for the effects of intentional forgetting. Some research, however, hypothesized that the time to process information mediates the underlying mechanism. To test this hypothesis, the current study investigated associations between oscillatory power in theta (3–7.5 Hz) and alpha frequencies (8–13 Hz) and intentional forgetting in human participants and explored whether or not these mechanisms depended on processing time. Previously, theta power was shown to be associated with the creation of episodic memory traces and alpha power with inhibition. We therefore expected to find associations between these neural signatures and behavioral effects. Consistent with our hypotheses, we revealed increased theta power for to-be-remembered and increased al...

At rest, mammalian brains display remarkable spatiotemporal complexity, evolving through recurrent functional connectivity ( FC ) states on a slow timescale of the order of tens of seconds. While the phenomenology of the resting state dynamics is valuable in distinguishing healthy and pathologic brains, little is known about its underlying mechanisms. Here, we identify neuronal cascades as a potential mechanism. Using full-brain network modeling, we show that neuronal populations, coupled via a detailed structural connectome, give rise to large-scale cascades of firing rate fluctuations evolving at the same time scale of resting-state networks ( RSNs ). The ignition and subsequent propagation of cascades depend on the brain state and connectivity of each region. The largest cascades produce bursts of blood oxygen level-dependent (BOLD) co-fluctuations at pairs of regions across the brain, which shape the simulated RSN dynamics. We experimentally confirm these theoretical predictions. We demonstrate the exi...

Signal transmission in the brain propagates via distinct oscillatory frequency bands but the aperiodic component, 1/f activity, almost always co-exists which most of the previous studies have not sufficiently taken into consideration. We used a recently proposed parameterization model that delimits the oscillatory and aperiodic components of neural dynamics on lifespan aging data collected from human participants using magnetoencephalography (MEG). Since healthy aging underlines an enormous change in local tissue properties, any systematic relationship of 1/f activity would highlight their impact on the self-organized critical functional states. Furthermore, we have used patterns of correlation between aperiodic background and metrics of behavior to understand the domain general effects of 1/f activity. We suggest that age-associated global change in 1/f baseline alters the functional critical states of the brain affecting the global information processing impacting critically all aspects of cognition, e.g...

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 noninvasive 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 nonspecialist and nontechnical operators. Because a modern web browser is the only software requirement, this choice is of great interest given its easy deployment and setup 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 to state-of-the-art commercial devices.