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...

Aggression may be behaviorally distinguished by reactive or appetitive properties. Here, we use a model of operant aggression administration, in which outbred male CD-1 mice lever press (contingent) or do not lever press (noncontingent) to attack an intruder mouse, to examine behavioral differences in aggression reinforcement. Contingent reinforcement identifies the behavioral and neural basis of appetitive, or rewarding, aggression self-administration, while noncontingent reinforcement isolates reactive, or involuntary, components. Females are not used in this study due to their low propensity to attack. We applied supervised machine-guided behavioral classification and Shapley additive scores (SHAP) to describe differences and similarities in attack behavior features. We find that behavioral sequences of an attack bout are similar whether aggression reinforcement is contingent or noncontingent, though underlying neural mechanisms differ. Fos immunolabeling following operant reinforcement reveals distinct...

Implicit sequence and visuomotor skill learning is important for successful goal-directed behavior in everyday tasks. However, prior research has primarily relied on correlational methods to investigate the underlying neural mechanisms of sequence and visuomotor skill learning. To evaluate the necessary contributions of different motor cortical regions to both types of skill learning, we enrolled 62 neurotypical adults (41 females, 21 males) and delivered spatiotemporally resolved single-pulse transcranial magnetic stimulation (TMS) over either the premotor cortex (PMC) or primary motor cortex (M1) to transiently disrupt activity while participants practiced an implicit motor sequence task. We hypothesized that (1) PMC disruption would preferentially reduce sequence-specific skill acquisition (Experiment 1) and retention (Experiment 2), while (2) M1 disruption would diminish visuomotor skill acquisition and retention but not sequence learning. Our results demonstrated that TMS-based interference over both ...

Neuronal populations connected by gap junctions can be revealed via dye coupling of small molecules like neurobiotin and Lucifer yellow. However, the extent of dye diffusion between neurons varies with connexin subtype, loading method, and neuromodulation. Due to the increasing availability of GCaMP transgenic animals, we explore the possibility of revealing gap junctional coupling using Ca2+ imaging in the motor system of Xenopus laevis tadpole of either sex. Reliable axo-axonal electrical coupling was previously found in excitatory descending interneurons (dINs) using paired recordings but not with neurobiotin dye coupling. Here, we made whole-cell patch–clamp recordings with Ca2+-supplemented intracellular solution to load Ca2+ into GCaMP6-expressing neurons, followed by Ca2+ imaging to detect potential Ca2+ diffusion across coupled neurons. Successful membrane breakthroughs led to transient fluorescence increases in the patched neuron. However, increasing the Ca2+ concentration promoted membrane reseal...

Sensorimotor adaptation depends on implicit recalibration and explicit strategy. These processes are commonly assumed to sum ( A  =  I  +  E ), and this additivity assumption justifies subtractive measurement and informs computational models of motor learning. Recent work has challenged additivity by examining regression slopes between implicit and explicit measures. When slopes deviate from β  = −1, the interpretation has been that the processes are “sub-additive” and fail to sum as expected. Here, we show this reasoning is mistaken. Regression slopes reflect covariance structure: how learning processes relate across individuals. Additivity is a claim about motor output combination: whether learning processes sum within individuals. These are different questions, and regression slopes do not address the latter. We derive the expected slope under subtractive logic and show it equals β  = −1 only when total adaptation is uncorrelated with the measured component. Monte Carlo simulations confirm this benchmar...

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...

This study used machine learning to objectively identify seizures in the electroencephalogram of a model of post-traumatic epilepsy based on fluid percussion injury in male rats. We applied transfer learning to a neural-network trained and tested on three potentially distinct electroencephalographic phenotypes: (1) late-onset convulsive seizures associated with rare post-traumatic epilepsy, (2) early-onset convulsive seizures that often occurred after sham or injury treatment (independent of post-traumatic epilepsy), and (3) spike-wave discharges, which occurred in both injured and sham-control rats. The neural network was able to detect seizure events within individual animals and across different cohorts and showed that early and late seizures have similar electroencephalographic phenotypes. Additionally, crossover training and testing on spike-wave discharges from injured and sham-control rats distinguished a convulsive-seizure phenotype from normal spike-wave discharges. Convolutional neural network mo...

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 pair-wise 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, 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 impa...

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) synapses and potentiate of non-nociceptive pressure (P) 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 hydrolase (FAAH), the enzyme t...