Opioid drugs are increasingly being prescribed to pregnant women. Such compounds can also bind and activate opioid receptors in the fetal brain, which could lead to long-term brain and behavioral disruptions. We hypothesized that maternal treatment with oxycodone (OXY), the primary opioid at the center of the current crisis, leads to later neurobehavioral disorders and gene expression changes in the hypothalamus and hippocampus of resulting offspring. Female mice were treated daily with 5 mg OXY/kg or saline solution (control; CTL) for two weeks before breeding and then throughout gestation. Male and female offspring from both groups were tested with a battery of behavioral and metabolic tests to measure cognition, exploratory-like, anxiety-like, voluntary physical activity, and socio-communication behaviors. qPCR analyses were performed for candidate gene expression patterns in the hypothalamus and hippocampus of OXY and CTL derived offspring. Developmental exposure to OXY caused socio-communication chang...

There is molecular, electrophysiological, and ultrastructural evidence that a net increase in synaptic strength occurs in many brain circuits during spontaneous wake (SW) or short sleep deprivation, reflecting ongoing learning. Sleep leads instead to a broad but selective weakening of many forebrain synapses, thus preventing synaptic saturation and decreasing the energy cost of synaptic activity. Whether synaptic potentiation can persist or further increase after long sleep deprivation is unknown. Whether synaptic renormalization can occur during chronic sleep restriction (CSR) is also unknown. Here, we addressed these questions by measuring an established ultrastructural measure of synaptic strength, the axon-spine interface (ASI), in the primary motor cortex (M1) of (1) one-month-old adolescent mice CSR using a paradigm that decreases NREM and REM sleep by two/thirds; (2) in two-week-old mouse pups sleep deprived for 15 h, or allowed afterward to recover for 16 h. Both groups were compared with mice of t...

Highlighted Research Paper: [[Lewis AS, Calipari ES, Siciliano CA (2021) Toward Standardized Guidelines for Investigating Neural Circuit Control of Behavior in Animal Research.][2]][2] []: /lookup/doi/10.1523/ENEURO.0498-20.2021

Dopamine replacement by levodopa (L-DOPA) is the most widely used therapy for Parkinson’s disease (PD), however patients often develop side effects, known as L-DOPA-induced dyskinesia (LID), that usually need therapeutic intervention. There are no suitable therapeutic options for LID, except for the use of the NMDA receptor (NMDA-R) antagonist amantadine, which has limited efficacy. The NMDA-R is indeed the most plausible target to manage LID in PD and recently the kinase Fyn, one of its key regulators, became a new putative molecular target involved in LID. The aim of this work was to reduce Fyn expression to alleviate LID in a mouse model of PD. We performed intrastriatal delivery of a designed micro-RNA against Fyn (miRNA-Fyn) in 6-OHDA-lesioned mice treated with L-DOPA. The miRNA-Fyn was delivered either before or after L-DOPA exposure to assess its ability to prevent or revert dyskinesia. Preadministration of miRNA-Fyn reduced LID with a concomitant reduction of FosB-ΔFosB protein levels, a marker of ...

Substantia nigra pars compacta (SNc) dopaminergic (DA) neurons display a peculiar electrical phenotype characterized in vitro by a spontaneous tonic regular activity (pacemaking activity), a broad action potential (AP) and a biphasic postinhibitory response. The transient A-type current (IA) is known to play a crucial role in this electrical phenotype, and so far, this current was considered to be carried exclusively by Kv4.3 potassium channels. Using Kv4.3−/− transgenic mice, we demonstrate that the constitutive loss of this channel is associated with increased exploratory behavior and impaired motor learning at the behavioral level. Consistently, it is also associated with a lack of compensatory changes in other ion currents at the cellular level. Using antigen retrieval (AR) immunohistochemistry, we then demonstrate that Kv4.2 potassium channels are also expressed in SNc DA neurons, although their contribution to IA appears significant only in a minority of neurons (∼5–10%). Using correlative analysis o...

The inflexible repetitive behaviors and “insistence on sameness” seen in autism imply a defect in neural processes controlling the balance between stability and plasticity of synaptic connections in the brain. It has been proposed that abnormalities in the Ras-ERK/MAPK pathway, a key plasticity-related cell signaling pathway known to drive consolidation of clustered synaptic connections, underlie altered learning phenotypes in autism. However, a link between altered Ras-ERK signaling and clustered dendritic spine plasticity has yet to be explored in an autism animal model in vivo . The formation and stabilization of dendritic spine clusters is abnormally increased in the MECP2-duplication syndrome mouse model of syndromic autism, suggesting that ERK signaling may be increased. Here, we show that the Ras-ERK pathway is indeed hyperactive following motor training in MECP2-duplication mouse motor cortex. Pharmacological inhibition of ERK signaling normalizes the excessive clustered spine stabilization and enh...

Depth sensitivity has been shown to be modulated by object context (plausibility). It is possible that it is behavioral relevance rather than object plausibility per se which drives this effect. Here, we manipulated the biological relevance of objects (face or a non-face) and tested whether object relevance affects behavioral sensitivity and neural responses to depth-position. In a first experiment, we presented human observers with disparity-defined faces and non-faces, and observers were asked to judge the depth position of the target under signal-noise and clear (fine) task conditions. In the second experiment, we concurrently measured behavioral and fMRI responses to depth. We found that behavioral performance varied across stimulus conditions such that they were significantly worse for the upright face than the inverted face and the random shape in the signal-to-noise (SNR) task, but worse for the random shape than the upright face in the feature task. Pattern analysis of fMRI responses revealed that ...

Most models of neural responses are constructed to reproduce the average response to inputs but lack the flexibility to capture observed variability in responses. The origins and structure of this variability have significant implications for how information is encoded and processed in the nervous system, both by limiting information that can be conveyed and by determining processing strategies that are favorable for minimizing its negative effects. Here, we present a new modeling framework that incorporates multiple sources of noise to better capture observed features of neural response variability across stimulus conditions. We apply this model to retinal ganglion cells at two different ambient light levels and demonstrate that it captures the full distribution of responses. Further, the model reveals light level-dependent changes that could not be seen with previous models, showing both large changes in rectification of nonlinear circuit elements and systematic differences in the contributions of differ...

Congenital sensorineural hearing loss (SNHL) affects thousands of infants each year and results in significant delays in speech and language development. Previous studies have shown that early exposure to a simple augmented acoustic environment (AAE) can limit the effects of progressive SNHL on hearing sensitivity. However, SNHL is also accompanied by hearing loss that is not assessed on standard audiological examinations, such as reduced temporal processing acuity. To assess whether sound therapy may improve these deficits, a mouse model of congenital SNHL was exposed to simple or temporally complex AAE. The DBA/2J mouse strain develops rapid, base to apex, progressive SNHL beginning at birth and is functionally deaf by six months of age. Hearing sensitivity and auditory brainstem function was measured using otoacoustic emissions, auditory brainstem response (ABR) and extracellular recording from the inferior colliculus (IC) in mice following exposure to 30 d of continuous AAE. Peripheral function and sou...

In the central and peripheral nervous systems, the myelin sheath promotes neuronal signal transduction. The thickness of the myelin sheath changes during development and in disease conditions like multiple sclerosis. Such changes are routinely detected using electron microscopy through g -ratio quantification. While g -ratio is one of the most critical measurements in myelin studies, a major drawback is that g -ratio quantification is extremely laborious and time-consuming. Here, we report the development and validation of MyelTracer, an installable, stand-alone software for semi-automated g -ratio quantification based on the Open Computer Vision Library (OpenCV). Compared with manual g -ratio quantification, using MyelTracer produces consistent results across multiple tissues and animal ages, as well as in remyelination after optic nerve crush, and reduces total quantification time by 40–60%. With g -ratio measurements via MyelTracer, a known hypomyelination phenotype can be detected in a Williams syndrom...