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...

Human infants who suffer from intrauterine growth restriction (IUGR), which is a failure to attain their genetically predetermined weight, are at increased risk for postnatal learning and memory deficits. Hippocampal dentate gyrus (DG) granule neurons play an important role in memory formation; however, it is unknown whether IUGR affects embryonic DG neurogenesis, which could provide a potential mechanism underlying abnormal postnatal learning and memory function. Using a mouse model of the most common cause of IUGR, induced by hypertensive disease of pregnancy, we first assessed adult learning and memory function. We quantified the percentages of embryonic hippocampal DG neural stem cells (NSCs) and progenitor cells and developing glutamatergic granule neurons, as well as hippocampal volumes and neuron cell count and morphology 18 and 40 d after delivery. We characterized the differential embryonic hippocampal transcriptomic pathways between appropriately grown and IUGR mouse offspring. We found that IUGR...

Knee joint trauma can cause an osteochondral defect (OD), a risk factor for osteoarthritis (OA) and cause of debilitating pain in patients. Rodent OD models are less translatable because of their smaller joint size and open growth plate. This study proposes sheep as a translationally relevant model to understand the neuronal basis of OD pain. A unilateral 6-mm deep OD was induced in adult female sheep. Two to six weeks after operation, lumbar dorsal root ganglia (DRG) neurons were collected from the contralateral (Ctrl) and OD side of operated sheep. Functional assessment of neuronal excitability and activity of the pain-related ion channels transient receptor potential vanilloid receptor 1 (TRPV1) and P2X3 was conducted using electrophysiology and Ca2+ imaging. Immunohistochemistry was used to verify expression of pain-related proteins. We observed that an increased proportion of OD DRG neurons (sheep, N  = 3; Ctrl neurons, n  = 15, OD neurons, n  = 16) showed spontaneous electrical excitability (Ctrl: 20...

The ability to adapt under significant adversity, defined as psychological resilience, is instrumental in preventing stress-related disorders. An important aspect of resilience is the capacity to endure affective distress when in pursuit of goals, also known as distress tolerance. Evidence that links intrinsic baseline interactions within large-scale functional networks with performance under distress remains missing. We hypothesized that the anterior cingulate cortex (ACC) may engage in distress tolerance because of its involvement in attention and emotion regulation. Accordingly, we tested whether behavioral performance under distress is associated with baseline resting-state ACC functional connectivity (FC). Distress tolerance was measured in 97 participants using the behavioral indicator of resiliency to distress (BIRD) task. Analyses contrasted participants who quit the task before its designated termination ( n  = 51) with those who persisted throughout it ( n  = 46). Seed-based FC analysis indicated...

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...

Frustrative nonreward (FN) is a construct in the Negative Valence Systems domain of the Research Domain Criteria (RDoC) from the National Institute of Mental Health. An organism’s response to frustrating situations (e.g., inability to obtain an expected reward) has broad implications for a variety of neuropsychiatric conditions, including substance use disorders. The current project developed a first of its kind rat operant behavioral model of FN based loosely on the human Point Subtraction Aggression Paradigm (PSAP). The current study shows that individual differences in FN for sucrose pellets are consistent across sessions at baseline and that the task is sensitive to reward size in male rats. More importantly, high FN behavior for sucrose predicts early “breaking” for intravenous fentanyl self-administration under a progressive ratio (PR) schedule. These results solidify frustration/ FN as an important factor for substance use disorders in addition to craving, impulsivity, and habit.

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.

Glycogen synthase kinase 3 (GSK3) proteins (GSK3α and GSK3β) are key mediators of signaling pathways, with crucial roles in coordinating fundamental biological processes during neural development. Here we show that the complete loss of GSK3 signaling in mouse retinal progenitors leads to microphthalmia with broad morphologic defects. A single wild-type allele of either Gsk3α or Gsk3β is able to rescue this phenotype. In this genetic context, all cell types are present in a functional retina. However, we unexpectedly detected a large number of cells in the inner nuclear layer expressing retinal ganglion cell (RGC)-specific markers (called displaced RGCs, dRGCs) when at least one allele of Gsk3α is expressed. The excess of dRGCs leads to an increased number of axons projecting into the ipsilateral medial terminal nucleus, an area of the brain belonging to the non-image-forming visual circuit and poorly targeted by RGCs in wild-type retina. Transcriptome analysis and optomotor response assay suggest that at l...

The nonhuman primate (NHP) constitutes an extraordinarily important model in neuroscience research for understanding the neuronal underpinnings of perceptual, motor, cognitive, and executive functions of the primate brain, and to study the physiological causes, effects, and potential treatments of brain disorders. Because of their cognitive capabilities, NHPs receive special attention in animal welfare regulations around the world, and their well-being is a benchmark for the evaluation, monitoring, and refinement of experimental procedures. As a consequence, many typical neuroscientific procedures are considered only mildly severe by animal welfare boards. There is, however, an ongoing debate about possible long-term and cumulative effects. Because of a lack of longitudinal data, it is unclear whether mildly severe procedures may cause more significant harm on the long-term, and to what extent they may impact animal well-being and healthiness over time. We here make use of a database of blood samples drawn...