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...

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...

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,...

Social connections in gregarious species are vital for safety and survival. For these reasons, many bird species form large flocks outside the breeding season. It has been proposed that such large social groups may be maintained via reward induced by positive interactions with conspecifics and via the reduction of a negative affective state caused by social separation. Moreover, within a flock optimal social spacing between conspecifics is important, indicating that individuals may optimize spacing to be close but not too close to conspecifics. The μ-opioid receptors (MORs) in the nucleus accumbens (NAc) are well known for their role in both reward and the reduction of negative affective states, suggesting that MOR stimulation in NAc may play a critical role in flock cohesion. To begin to test this hypothesis, social and nonsocial behaviors were examined in male and female European starlings ( Sturnus vulgaris ) in nonbreeding flocks after intra-NAc infusion of saline and three doses of the selective MOR a...

The perirhinal (PER) and postrhinal (POR) cortices, structures in the medial temporal lobe, are implicated in learning and memory. The PER is understood to process object information and the POR to process spatial or contextual information. Whether the medial temporal lobe is dedicated to memory, however, is under debate. In this study, we addressed the hypothesis that the PER and POR are also involved in non-mnemonic cognitive functions. Rats with PER or POR damage and SHAM surgical controls were shaped, trained, and tested on the five-choice serial reaction time (5CSRT) task, which assesses attention and executive function. Rats with PER damage were impaired in acquiring the task and at asymptote, although processing information about objects was not relevant to the task. When confronted with attentional challenges, rats with PER damage showed a pattern consistent with decreased attentional capacity, increased response errors, and increased impulsive behavior. Rats with POR damage showed intact acquisiti...

In recent years there has been extensive research on malformations of cortical development (MCDs) that result in clinical features like developmental delay, intellectual disability, and drug-resistant epilepsy (DRE). Various studies highlighted the contribution of microtubule-associated genes (including tubulin and kinesin encoding genes) in MCD development. It has been reported that de novo mutations in KIF2A , a member of the kinesin-13 family, are linked to brain malformations and DRE. Although it is known that KIF2A functions by regulating microtubule depolymerization via an ATP-driven process, in vivo implications of KIF2A loss of function remain partly unclear. Here, we present a novel kif2a knock-out zebrafish model, showing hypoactivity, habituation deficits, pentylenetetrazole-induced seizure susceptibility and microcephaly, as well as neuronal cell proliferation defects and increased apoptosis. Interestingly, kif2a −/− larvae survived until adulthood and were fertile. Notably, our kif2a zebrafish...

Opsin 3 ( Opn3 ) is highly expressed in the adult brain, however, information for spatial and temporal expression patterns during embryogenesis is significantly lacking. Here, an Opn3 -eGFP reporter mouse line was used to monitor cell body expression and axonal projections during embryonic and early postnatal to adult stages. By applying 2D and 3D fluorescence imaging techniques, we have identified the onset of Opn3 expression, which predominantly occurred during embryonic stages, in various structures during brain/head development. In addition, this study defines over twenty Opn3 -eGFP-positive neural structures never reported before. Opn3 -eGFP was first observed at E9.5 in neural regions, including the ganglia that will ultimately form the trigeminal, facial and vestibulocochlear cranial nerves (CNs). As development proceeds, expanded Opn3 -eGFP expression coincided with the formation and maturation of critical components of the central and peripheral nervous systems (CNS, PNS), including various motor-...