Spiking thresholds in neurons or rectification at synapses are essential for neuronal computations rendering neuronal processing inherently nonlinear. Nevertheless, linear response theory has been instrumental for understanding, for example, the impact of noise or neuronal synchrony on signal transmission, or the emergence of oscillatory activity, but is valid only at low stimulus amplitudes or large levels of intrinsic noise. At higher signal-to-noise ratios, however, nonlinear response components become relevant. Theoretical results for leaky integrate-and-fire neurons in the weakly nonlinear regime suggest strong responses at the sum of two input frequencies if one of these frequencies or their sum matches the neuron’s baseline firing rate. We here analyze nonlinear responses in two types of primary electroreceptor afferents, the P-units of the active and the ampullary cells of the passive electrosensory system of the wave-type electric fish Apteronotus leptorhynchus of either sex. In our combined exper...

Synaptic physiology experiments are fundamental to neuroscience research. Consequently, accurate detection of synaptic currents is crucial for conducting high-quality experiments. Traditionally, detecting inhibitory and excitatory postsynaptic currents (sIPSCs/sEPSCs) relied on hand-counting individual events. Although sEPSCs and sIPSCs are clear to the trained eye, hand analysis is time and labor intensive. Recent advances in applied machine learning promise faster, superior event detectors that may improve data quality and reduce or even completely negate the need for hand curation. While many strategies for sIPSC and sEPSC detection exist, rarely have they been quantitatively compared for accuracy within an experiment. Our study aims to establish practical ground-truth event detection in a large experimental dataset through meticulous hand counting and to assess variance in detection results across different laboratories, analysis techniques, and cell types. Using thoroughly hand-counted data as our gro...

We describe a novel method for adapting a two-photon scanning microscope to enable simultaneous detection of two-photon-generated visible fluorescence and single-photon-generated near-infrared (nIR) fluorescence. In this configuration, nIR fluorescence is routed through a single-mode optical fiber before detection by a photomultiplier tube. This fiber coupling offers two advantages: first, the optical fiber functions as a pinhole aperture, allowing for improved optical sectioning of the nIR signal; second, it minimizes nIR background fluorescence. To validate the effectiveness of this design, we conducted two sets of experiments in male and female C57B/6J mice. First, we compare two fluorescence indicators of the neurotransmitter dopamine: the genetically encoded indicator GRABDA and single-walled carbon nanotube-based optical nanosensors (nIRCats). Although nIRCats exhibit lower affinity for dopamine than GRABDA, this property allows for identification of high concentration release sites in the striatum. ...

Olfactory anhedonia and heightened aversion to unpleasant odors are well-documented features of depression in humans, yet the neural mechanisms linking chronic stress to altered olfactory perception remain poorly understood. We used the unpredictable chronic mild stress (UCMS) paradigm to examine how chronic stress affects olfactory avoidance behavior and glial cell morphology across multiple olfactory brain regions in male and female mice. UCMS-treated mice showed increased avoidance of aversive odorants in an odorized light/dark box assay, consistent with heightened aversive reactivity to odors following chronic stress. Using immunohistochemistry, we assessed microglial morphology and astrocyte density across six olfactory and limbic brain regions. Chronic stress produced region-specific glial remodeling: astrocyte counts were selectively elevated in the medial amygdala, and microglial process complexity was increased in the anterior olfactory nucleus and anterior piriform cortex. Microglial morphologica...

There is considerable interest in cannabinoid-based therapies to treat pain, but activation of the endogenous cannabinoid (endocannabinoid) system can elicit pro- and anti-nociceptive effects. This study tests the hypothesis that the concentration of the endocannabinoid arachidonoylethanolamine (AEA) contributes to whether pro- or anti-nociceptive effects are observed. Experiments were carried out using isolated ganglia from the medicinal leech Hirudo verbana where it is possible to selectively record from nociceptive and non-nociceptive synapses in the central nervous system (CNS). Previous studies using Hirudo have shown that endocannabinoids depress nociceptive (N) sensory cell synapses and potentiate of non-nociceptive pressure (P) sensory cell synapses. In this study, exogenously applied AEA produced depression of N synapses and potentiation of P synapses across the same range of concentrations. However, the results differed when using URB597, a drug that raises AEA by inhibiting fatty acid amine hydr...

Multi-electrode recording of neuronal activity in cultures offer opportunities for understanding how the structure of a network gives rise to function. Neuronal cultures derived from human induced pluripotent stem cells (iPSCs) from male and female individuals are often plated at highly variable cell densities across studies, but its impact on neuronal activity remains poorly understood. We found that properties such as the mean firing rate of the individual cells, the pairwise correlations between cells, and the entropy of the population all changed significantly with changes in culture density. We used a maximum entropy model to capture the structure of the population activity using only the firing rates and correlations, and we found that the model performed best at the highest densities, suggesting that changes in activity reflected differences in structure of interactions between neurons across scales of complexity. Our work thus shows that culture density is an important experimental parameter that i...

Complex problems often allow multiple paths to a solution. Choosing and taking the best path is an important part of the executive cognition that underpins intelligent problem-solving behavior. However, once a path is chosen, the motor system must be activated for executing it. This interface between problem-solving and self-generated action has rarely been studied. We recorded EEG movement-related potentials while 25 participants (7 males, 18 females) performed the “Tower of London” problem-solving task. In a control condition, participants merely followed instructed steps without planning for any goal and thus without any sense that their movements solved a problem. Readiness potentials (RPs) preceding actions showed a more sustained preparatory negativity for self-generated than stimulus-driven movements. Critically, this effect was most pronounced at the first move of a sequence and diminished at later stages, indicating that preparatory activity is closely linked to the planning demands of sequence in...

Dr. Ann McKee will describe the emergence of chronic traumatic encephalopathy (CTE) as a distinct disease over the past 20 years.

Ischemic stroke, a leading cause of neurological morbidity, is characterized by extensive neuronal injury and a robust inflammatory response. Erbin, a scaffold protein involved in multiple cellular signaling pathways, regulates neuroinflammation and may confer neuroprotection against ischemia-reperfusion (I/R) injury. A mouse model of middle cerebral artery occlusion (MCAO) was utilized to evaluate the neuroprotective role of Erbin. Male mice were allocated into groups receiving either a lentiviral (LV) control vector or LV-mediated Erbin overexpression, followed by I/R injury induction. Neurological function, infarct volume, and expression levels of inflammatory cytokines and mitogen-activated protein kinase (MAPK) signaling proteins were analyzed. Overexpression of Erbin via LV transduction significantly reduced cerebral infarct volume and mitigated neurological impairments post-I/R injury. Furthermore, Erbin overexpression suppressed the phosphorylation of p38 and extracellular signal-regulated kinase (...

The amount of time previously spent awake or asleep strongly impacts the sleep electroencephalogram (EEG), especially slow waves during non-rapid-eye-movement (NREM) sleep. These effects on the sleep EEG meaningfully interact with age and to a lesser extent developmental disorders such as attention-deficit hyperactivity disorder (ADHD). We aimed to determine whether EEG oscillations during wakefulness were likewise affected by the interaction of sleep and development, using data collected from 163 participants 3-25 years old (62 female). We analyzed age- and sleep-dependent changes in two measures of oscillatory activity (amplitudes and density) and aperiodic activity (offsets and exponents). Finally, we compared wake EEG in children with ADHD (N=58) to neurotypical controls, with habitual good sleep quality required for inclusion. We found that oscillation amplitudes exhibited the same dynamics as sleep slow waves: decreasing with age, decreasing after sleep, and the overnight decrease decreasing with age...