The levels of voltage-gated and synaptic currents in the same neuron type can vary substantially across individuals. Yet, the phase relationships between neurons in oscillatory circuits are often maintained, even in the face of varying oscillation frequencies. We examined whether synaptic and intrinsic currents are matched to maintain constant activity phases across preparations, using the lateral pyloric (LP) neuron of the stomatogastric ganglion (STG) of the crab, Cancer borealis . LP produces stable oscillatory bursts on release from inhibition, with an onset phase that is independent of oscillation frequency. We quantified the parameters that define the shape of the synaptic current inputs across preparations and found no linear correlations with voltage-gated currents. However, several synaptic parameters were correlated with oscillation period and burst onset phase, suggesting they may play a role in phase maintenance. We used dynamic clamp to apply artificial synaptic inputs and found that those syn...

Recent studies using intracellular recordings in awake behaving mice revealed that cortical network states, defined based on membrane potential features, modulate sensory responses and perceptual outcomes. Single-cell intracellular recordings are difficult and have low yield compared to extracellular recordings of population signals, such as local field potentials (LFPs). However, it is currently unclear how to identify these behaviorally-relevant network states from the LFP. We used simultaneous LFP and intracellular recordings in the somatosensory cortex of awake mice to design a network state classification from the LFP, the Network State Index (NSI). We used the NSI to analyze the relationship between single-cell (intracellular) and population (LFP) signals over different network states of wakefulness. We found that graded levels of population signal faithfully predicted the levels of single-cell depolarization in nonrhythmic regimes whereas, in δ ([2–4 Hz]) oscillatory regimes, the graded levels of rh...

Neurofilaments are abundant space-filling cytoskeletal polymers that are transported into and along axons. During postnatal development, these polymers accumulate in myelinated axons causing an expansion of axon caliber, which is necessary for rapid electrical transmission. Studies on cultured nerve cells have shown that axonal neurofilaments move rapidly and intermittently along microtubule tracks in both anterograde and retrograde directions. However, it is unclear whether neurofilament transport is also bidirectional in vivo . Here, we describe a pulse-spread fluorescence photoactivation method to address this in peripheral nerves dissected from hThy1-paGFP-NFM transgenic mice, which express a photoactivatable fluorescent neurofilament protein. Neurofilaments were photoactivated in short segments of myelinated axons in tibial nerves at 2, 4, 8, and 16 weeks of age. The proximal and distal spread of the fluorescence due to the movement of the fluorescent neurofilaments was measured over time. We show tha...

Seizures cause retrograde amnesia. We have previously demonstrated that seizures erode recently formed memories through shared ensembles and mechanisms in the CA1 region of the hippocampus. Here, we tested whether seizure circuits overlap spatial memory circuits outside of the CA. Spatial memory is consolidated by the hippocampal-cortical coupling that are connected via multiple pathways. We tested whether a seizure invades structures involved in memory consolidation by using the activity reporter TRAP2 mice. T-maze alternation learning activated neurons in the dentate gyrus (DG), mediodorsal thalamus (MD), retrosplenial cortex (RSC), and medial prefrontal cortex (mPFC). This spatial memory relies on the plasticity of the AMPA receptor GluA1 subunit. GluA1 knock-out (KO)/TRAP2 mice did not learn to alternate, and structures interposed between the hippocampus and the cortex were not active. A seizure prevented the recall of alternation memory and activated memory-labeled structures. There was a widespread o...

There are currently no Food and Drug Administration (FDA)-approved δ-opioid receptor (DOR)-selective agonists, despite having fewer side effects in rodents and nonhuman primates compared with traditional μ-opioid receptor (MOR) therapeutics ([Vanderah, 2010][1]). Targeting peripheral receptors is an attractive strategy to reduce abuse potential. However, peripheral opioid receptors do not readily respond to agonists unless primed by inflammation, which would limit their efficacy in noninflammatory pain patients ([Stein et al., 1989][2]). It was recently identified that G-protein-coupled receptor kinase 2 (GRK2) maintains DOR incompetence in noninflamed nociceptors ([Brackley et al., 2016][3], [2017][4]). Here, we report that paroxetine, a selective serotonin reuptake inhibitor (SSRI) and potent GRK2 inhibitor ([Thal et al., 2012][5]), reduces chronic GRK2 association with membrane DOR, thereby enhancing peripheral DOR-mediated analgesic competence in the absence of inflammation. Interestingly, paroxetine’s...

Altered lipoprotein metabolism is considered a pathogenic component of amyotrophic lateral sclerosis (ALS). Apolipoprotein A1 (ApoA1), a major high-density lipoprotein (HDL) protein, is associated with prevention of vascular damage. However, ApoA1’s effects on damaged endothelium in ALS are unknown. This study aimed to determine therapeutic potential of ApoA1 for endothelial cell (EC) repair under a pathologic condition reminiscent of ALS. We performed in vitro studies using mouse brain ECs (mBECs) exposed to plasma from symptomatic G93A SOD1 mice. Dosage effects of ApoA1, including inhibition of the phosphoinoside 3-kinase (PI3K)/Akt signaling pathway and integration of ApoA1 into mBECs were examined. Also, human bone marrow-derived endothelial progenitor cells (hBM-EPCs) and mBECs were co-cultured without cell contact to establish therapeutic mechanism of hBM-EPC transplantation. Results showed that ApoA1 significantly reduced mBEC death via the PI3K/Akt downstream signaling pathway. Also, ApoA1 was inco...

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results in intellectual disability and, in ∼50% of patients, autism spectrum disorder. The protein products that are altered in TSC (TSC1 and TSC2) form a complex to inhibit the mammalian target of rapamycin [mTOR; mTOR complex 1 (mTORC1)] pathway. This pathway has been shown to affect the process of mRNA translation through its action on ribosomal protein S6 and 4-elongation binding protein 1. It is thought that mutations in the TSC proteins lead to upregulation of the mTORC1 pathway and consequently an increase in protein synthesis. Unexpectedly, our previous study of a mouse model of TSC ( Tsc2Djk +/−) demonstrated decreased in vivo rates of protein synthesis throughout the brain. In the present study, we confirm those results in another Tsc2 +/− mouse model, one with a different mutation locus and on a mixed background ( Tsc2Mjg +/−). We also examine mTORC1 signaling and possible effects of prior isoflurane anesthesia. Because meas...

A hallmark of human reaching movements is that they are appropriately tuned to the task goal and to the environmental context. This was demonstrated by the way humans flexibly respond to mechanical and visual perturbations that happen during movement. Furthermore, it was previously showed that the properties of goal-directed control can change within a movement, following abrupt changes in the goal structure. Such online adjustment was characterized by a modulation of feedback gains following switches in target shape. However, it remains unknown whether the underlying mechanism merely switches between prespecified policies, or whether it results from continuous and potentially dynamic adjustments. Here, we address this question by investigating participants’ feedback control strategies in presence of various changes in target width during reaching. More specifically, we studied whether the feedback responses to mechanical perturbations were sensitive to the rate of change in target width, which would be in...

Breastfeeding confers robust benefits to offspring development in terms of growth, immunity, and neurophysiology. Similarly, improving environmental complexity, i.e., environmental enrichment (EE), contributes developmental advantages to both humans and laboratory animal models. However, the impact of environmental context on maternal care and milk quality has not been thoroughly evaluated, nor are the biological underpinnings of EE on offspring development understood. Here, Sprague Dawley rats were housed and bred in either EE or standard-housed (SD) conditions. EE dams gave birth to a larger number of pups, and litters were standardized and cross-fostered across groups on postnatal day (P)1. Maternal milk samples were then collected on P1 (transitional milk phase) and P10 (mature milk phase) for analysis. While EE dams spent less time nursing, postnatal enrichment exposure was associated with heavier offspring bodyweights. Milk from EE mothers had increased triglyceride levels, a greater microbiome diver...

Electrophysiological oscillations in the brain have been shown to occur as multicycle events, with onset and offset dependent on behavioral and cognitive state. To provide a baseline for state-related and task-related events, we quantified oscillation features in resting-state recordings. We developed an open-source wavelet-based tool to detect and characterize such oscillation events (OEvents) and exemplify the use of this tool in both simulations and two invasively-recorded electrophysiology datasets: one from human, and one from nonhuman primate (NHP) auditory system. After removing incidentally occurring event-related potentials (ERPs), we used OEvents to quantify oscillation features. We identified ∼2 million oscillation events, classified within traditional frequency bands: δ, θ, α, β, low γ, γ, and high γ. Oscillation events of 1–44 cycles could be identified in at least one frequency band 90% of the time in human and NHP recordings. Individual oscillation events were characterized by nonconstant fr...