Humans can perform complex movements with speed and agility in the face of constantly changing task demands. To accomplish this, motor plans are adapted to account for errors in our movements due to changes in our body (e.g., growth or injury) or in the environment (e.g., walking on sand vs. ice). It has been suggested that adaptation that occurs in response to changes in the state of our body will generalize across different movement contexts and environments, whereas adaptation that occurs with alterations in the external environment will be context-specific. Here we asked if the ability to form generalizable versus context-specific motor memories develops during childhood. We performed a cross-sectional study of context-specific locomotor adaptation in 35 children (3-18 years old) and 7 adults (19-31 years old). Subjects first adapted their gait and learned a new walking pattern on a split-belt treadmill, which has two belts that move each leg at a different speed. Then, subjects walked overground to as...

The neural circuits that support human cognition are a topic of enduring interest. Yet, there are limited tools available to map human brain circuits in the human and non-human primate brain. We harnessed high-resolution diffusion MR tractography, anatomic, and transcriptomic data from individuals of either sex to investigate the evolution and development of frontal cortex circuitry. We applied machine learning to RNA sequencing data to find corresponding ages between humans and macaques and to compare the development of circuits across species. We transcriptionally defined neural circuits by testing for associations between gene expression and white matter maturation. We then considered transcriptional and structural growth to test whether frontal cortex circuit maturation is unusually extended in humans relative to other species. We also considered gene expression and high-resolution diffusion MR tractography of adult brains to test for cross-species variation in frontal cortex circuits. We found that fr...

Brain size significantly impacts the organization of white matter fibers. Fiber length scaling – the degree to which fiber length varies according to brain size – was overlooked. We investigated how fiber lengths within the corpus callosum, the most prominent white matter tract, vary according to brain size. The results showed substantial variation in length scaling among callosal fibers, replicated in two large healthy cohorts (∼2000 human subjects, including both sexes). The underscaled callosal fibers mainly connected the precentral gyrus and parietal cortices, whereas the overscaled callosal fibers mainly connected the prefrontal cortices. The variation in such length scaling was biologically meaningful: larger scaling corresponded to larger neurite density index but smaller fractional anisotropy values; cortical regions connected by the callosal fibers with larger scaling were more lateralized functionally as well as phylogenetically and ontogenetically more recent than their counterparts. These findi...

Many hippocampal CA1 pyramidal cells function as place cells, increasing their firing rate when a specific place field is traversed. The dependence of CA1 place cell firing on position within the place field is asymmetric. We investigated the source of this asymmetry by injecting triangular depolarizing current ramps to approximate the spatially-tuned, temporally-diffuse depolarizing synaptic input received by these neurons while traversing a place field. Ramps were applied to CA1 pyramidal neurons from male rats in vitro (slice electrophysiology) and in silico (multi-compartmental NEURON model). Under control conditions, CA1 neurons fired more action potentials at higher frequencies on the up-ramp versus the down-ramp. This effect was more pronounced for dendritic compared to somatic ramps. We incorporated a four-state Markov scheme for NaV1.6 channels into our model and calibrated the spatial dependence of long-term inactivation according to the literature; this spatial dependence was sufficient to expla...

Emerging evidence shows that spontaneous synaptic transmission plays crucial roles on neuronal functions through presynaptic molecular mechanisms distinct from that of action potential (AP)-evoked transmission. However, whether the synaptic vesicle (SV) population undergoing the two forms of transmission is segregated remains controversial due in part to the conflicting results observed in cultured neurons. Here we address this issue in intact neuromuscular synapses using transgenic zebrafish larvae expressing two different indicators targeted in the SVs: a pH-sensitive fluorescent protein, pHluorin, and a tag protein, HaloTag. By establishing a quantitative measure of recycled SV fractions, we found that approximately 85% of SVs were mobilized by high-frequency AP firings. In contrast, spontaneously recycling SVs were mobilized only from <8% of SVs with a time constant of 45 min at 25°C, although prolonged AP inhibition mobilized an additional population with a delayed onset. The mobilization of the early...

The opioid epidemic is a rapidly evolving societal issue driven, in part, by a surge in synthetic opioid use. A rise in fentanyl use among pregnant women has led to a 40-fold increase in the number of perinatally-exposed infants in the past decade. These children are more likely to develop mood- and somatosensory-related conditions later in life, suggesting that fentanyl may permanently alter neural development. Here, we examined the behavioral and synaptic consequences of perinatal fentanyl exposure in adolescent male and female C57BL/6J mice and assessed the therapeutic potential of environmental enrichment to mitigate these effects. Dams were given ad libitum access to fentanyl (10 µg/mL, per os ) across pregnancy and until weaning (PD 21). Perinatally-exposed adolescent mice displayed hyperactivity (PD 45), enhanced sensitivity to anxiogenic environments (PD 46), and sensory maladaptation (PD 47) – sustained behavioral effects that were completely normalized by environmental enrichment (PD 21-45). Addi...

Opioid use by pregnant women results in neonatal opioid withdrawal syndrome (NOWS) and lifelong neurobehavioral deficits including language impairments. Animal models of NOWS show impaired performance in a two-tone auditory discrimination task, suggesting abnormalities in sensory processing in the auditory cortex. To investigate the consequences of perinatal opioid exposure on auditory cortex circuits, we administered fentanyl to mouse dams in their drinking water throughout gestation and until litters were weaned at postnatal day (P) 21. We then used in vivo 2-photon Ca2+ imaging in adult animals of both sexes to investigate how primary auditory cortex (A1) function was altered. Perinatally exposed animals showed fewer sound-responsive neurons in A1, and the remaining sound-responsive cells exhibited lower response amplitudes but normal frequency selectivity and stimulus-specific adaptation. Populations of nearby layer 2/3 (L2/3) cells in exposed animals showed reduced correlated activity, suggesting a re...

Deactivation of G protein-coupled receptors (GPCRs) involves multiple phosphorylations followed by arrestin binding, which uncouples the GPCR from G protein activation. Some GPCRs, such as rhodopsin, are reused many times. Arrestin dissociation and GPCR dephosphorylation are key steps in the recycling process. In vitro evidence suggests that visual arrestin (Arr1) binding to light-activated, phosphorylated rhodopsin hinders dephosphorylation. Whether Arr1 binding also affects rhodopsin dephosphorylation in vivo is not known. We investigated this using both male and female mice lacking Arr1. Mice were exposed to bright light and placed in darkness for different periods of time, and differently phosphorylated species of rhodopsin were assayed by isoelectric focusing. For wildtype mice, rhodopsin dephosphorylation was nearly complete by one hour in darkness. Surprisingly, we observed that in the ARR1 knockout rods, rhodopsin remained phosphorylated even after three hours. Delayed dephosphorylation in ARR1 kno...

Electrocorticography (ECoG) methodologically bridges basic neuroscience and understanding of human brains in health and disease. However, the localization of ECoG signals across the surface of the brain and the spatial distribution of their generating neuronal sources are poorly understood. To address this gap, we recorded from rat auditory cortex using customized μECoG, and simulated cortical surface electrical potentials with a full-scale, biophysically detailed cortical column model. Experimentally, μECoG-derived auditory representations were tonotopically organized and signals were anisotropically localized to ≤±200 μm, i.e., a single cortical column. Biophysical simulations reproduce experimental findings, and indicate that neurons in cortical layers V and VI contribute ∼85% of evoked high-gamma signal recorded at the surface. Cell number and synchrony were the primary biophysical properties determining laminar contributions to evoked μECoG signals, while distance was only a minimal factor. Thus, evok...

In order to successfully forage in an environment filled with rewards and threats, animals need to rely on familiar structures of their environment that signal food availability. The central amygdala (CeA) is known to mediate a panoply of consummatory and defensive behaviors, yet how specific activity patterns within CeA subpopulations guide optimal choices is not completely understood. In a paradigm of appetitive conditioning in which mice freely forage for food across a continuum of cues, we found that two major subpopulations of CeA neurons, Somatostatin-positive (CeASst) and protein kinase Cδ-positive (CeAPKCδ) neurons can assign motivational properties to environmental cues. While the proportion of food responsive cells was higher within CeASst than CeAPKCδ neurons, only the activities of CeAPKCδ, but not CeASst, neurons were required for learning of contextual food cues. Our findings point to a model in which CeAPKCδ neurons may incorporate stimulus salience together with sensory features of the envi...