Our brains synthesize vast and varied sensory inputs to represent an event or place that can later be recalled freely. The term “engram” refers to a group of neurons activated in association with a memory or event, suggesting that if one were to activate a subset of cells in the ensemble, one would trigger the recall of a memory. The medial temporal lobes, including the hippocampus, are often studied as the primary region of spatial engram formation (Josselyn and Tonegawa, 2020). However, newly formed spatial memory representations are incredibly transient. Following encoding, consolidation from the hippocampus to related cortical structures is critical for stable memory retention (Wirt and Hyman, 2017). What happens when this process of generating stable long-term memories is disrupted? Neuronal hyperactivity, seen in seizures, potentially corrupts existing engrams and is often associated with retrograde amnesia in humans. Retrograde amnesia, or forgetting recently formed memories, could be because of dis...

Low-frequency (<200 Hz), subperception spinal cord stimulation (SCS) is a novel modality demonstrating therapeutic efficacy for treating chronic neuropathic pain. When stimulation parameters were carefully titrated, patients experienced rapid onset (seconds–minutes) pain relief without paresthesia, but the mechanisms of action are unknown. Using an integrated computational model and in vivo measurements in urethane-anesthetized rats, we quantified how stimulation parameters (placement, pulse width, frequency, and amplitude) influenced dorsal column (DC) axon activation and neural responses in the dorsal horn (DH). Both modeled and recorded DC axons responded with irregular spiking patterns in response to low-amplitude SCS. Maximum inhibition of DH neurons occurred at ∼80% of the predicted sensory threshold in both modeled and recorded neurons, and responses were strongly dependent on spatially targeting of stimulation, i.e., the complement of DC axons activated, and on stimulation parameters. Intrathecal a...

The ability to detect faces in the environment is of utmost ecological importance for human social adaptation. While face categorization is efficient, fast and robust to sensory degradation, it is massively impaired when the facial stimulus does not match the natural contrast statistics of this visual category, i.e., the typically experienced ordered alternation of relatively darker and lighter regions of the face. To clarify this phenomenon, we characterized the contribution of natural contrast statistics to face categorization. Specifically, 31 human adults viewed various natural images of nonface categories at a rate of 12 Hz, with highly variable images of faces occurring every eight stimuli (1.5 Hz). As in previous studies, neural responses at 1.5 Hz as measured with high-density electroencephalography (EEG) provided an objective neural index of face categorization. Here, when face images were shown in their naturally experienced contrast statistics, the 1.5-Hz face categorization response emerged ove...

It has been suggested that the dorsomedial striatum (DMS) is engaged in the early stages of motor learning for goal-directed actions, whereas at later stages, control is transferred to the dorsolateral striatum (DLS), a process that enables learned motor actions to become a skill or habit. It is not known whether these striatal regions are simultaneously active while the expertise is acquired. To address this question, we developed a mouse “Treadmill Training Task” that tracks changes in mouse locomotor coordination during running practice and simultaneously provides a means to measure local neuronal activity using photometry. To measure change in motor coordination over treadmill practice sessions, we used DeepLabCut (DLC) and custom-built code to analyze body position and paw movements. By evaluating improvements in motor coordination during training with simultaneous neuronal calcium activity in the striatum, we found that DMS direct pathway neurons exhibited decreased activity as the mouse gained profi...

Despite increased prevalence of maternal cannabis use, little is understood regarding potential long-term effects of prenatal cannabis exposure (PCE) on neurodevelopmental outcomes. While neurodevelopmental cannabis exposure increases the risk of developing affective/mood disorders in adulthood, the precise neuropathophysiological mechanisms in male and female offspring are largely unknown. Given the interconnectivity of the endocannabinoid (ECb) system and the brain’s fatty acid pathways, we hypothesized that prenatal exposure to Δ9-tetrahydrocannabinol (THC) may dysregulate fetal neurodevelopment through alterations of fatty-acid dependent synaptic and neuronal function in the mesolimbic system. To investigate this, pregnant Wistar rats were exposed to vehicle or THC (3 mg/kg) from gestational day (GD)7 until GD22. Anxiety-like, depressive-like, and reward-seeking behavior, electrophysiology, and molecular assays were performed on adult male/female offspring. Imaging of fatty acids using matrix-assisted ...

The development of validated algorithms for automated handling of artifacts is essential for reliable and fast processing of EEG signals. Recently, there have been methodological advances in designing machine-learning algorithms to improve artifact detection of trained professionals who usually meticulously inspect and manually annotate EEG signals. However, validation of these methods is hindered by the lack of a gold standard as data are mostly private and data annotation is time consuming and error prone. In the effort to circumvent these issues, we propose an iterative learning model to speed up and reduce errors of manual annotation of EEG. We use a convolutional neural network (CNN) to train on expert-annotated eyes-open and eyes-closed resting-state EEG data from typically developing children ( n = 30) and children with neurodevelopmental disorders ( n = 141). To overcome the circular reasoning of aiming to develop a new algorithm and benchmarking to a manually-annotated gold standard, we instead ai...

Considerable evidence from mouse models and human postmortem brain suggests loss of Muscleblind-like protein 2 (MBNL2) function in brain is a major driver of CNS symptoms in Myotonic dystrophy type 1 (DM1). Increased hypersomnia, fatigue, and surgical complications associated with general anesthesia suggest possible sensitivity to GABAergic inhibition in DM1. To test the hypothesis that MBNL2 depletion leads to behavioral sensitivity to GABAA receptor (GABAA-R) modulation, Mbnl2 knock-out (KO) and wild-type (WT) littermates were treated with the anesthetic sevoflurane, the benzodiazepine diazepam, the imidazopyridine zolpidem, and the benzodiazepine rescue agent, flumazenil (Ro 15-1788), and assessed for various behavioral metrics. Mbnl2 KO mice exhibited delayed recovery following sevoflurane, delayed emergence and recovery from zolpidem, and enhanced sleep time at baseline that was modulated by flumazenil. A significantly higher proportion of Mbnl2 KO mice also loss their righting reflex [loss of rightin...

Goal-tracking (GT) rats are sensitive to Pavlovian outcome devaluation while sign-tracking (ST) rats are devaluation insensitive. During outcome devaluation, GT rats flexibly modify responding to cues based on the current value of the associated outcome. However, ST rats rigidly respond to cues regardless of the current outcome value. Prior work demonstrated disconnection of the basolateral amygdala (BLA) and anterior insular cortex (aIC) decreased both GT and ST behaviors. Given the role of these regions in appetitive motivation and behavioral flexibility, we predicted that disrupting BLA to aIC pathway during outcome devaluation would reduce flexibility in GT rats and reduce rigid appetitive motivation in ST rats. We inhibited the BLA to aIC pathway by infusing inhibitory DREADDs (hM4Di-mcherry) or control (mCherry) virus into the BLA and implanted cannulae into the aIC to inhibit BLA terminals using intracranial injections of clozapine N-oxide (CNO). After training, we used a within - subject satiety-in...

Implantation of guide cannulas is a widely used technique to access specific brain areas. Although commercially available, the need to personalize these implants and the high cost prompted us to design open-source customized devices taking advantage of 3D printing technology. Our cannulas consisted in a 3D-printed head mount designed according to the Paxinos coordinates to reach the CA1 area of the hippocampus. To cut guide cannulas to the proper length, we designed and realized an original 3D-printed linear motion apparatus. Polylactic acid thermoplastic polymer was used as printing material. Homemade or commercial cannulas were implanted in 4- to 6-month-old wild-type mice and intrahippocampal injections of amyloid-β peptide at different concentrations were performed. In vivo behavioral studies of novel object recognition indicated that results obtained with homemade versus commercial devices were comparable. Methylene blue injections and Nissl staining confirmed the correct localization of cannulas in t...

The 1/ f spectral slope of the electroencephalogram (EEG) estimated in the γ frequency range has been proposed as an arousal marker that differentiates wake, nonrapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Here, we sought to replicate and extend these findings in a large sample, providing a comprehensive characterization of how slope changes with age, sex, and its test-retest reliability as well as potential confounds that could affect the slope estimation. We used 10,255 whole-night polysomnograms (PSGs) from the National Sleep Research Resource (NSRR). All preprocessing steps were performed using an open-source Luna package and the spectral slope was estimated by fitting log-log linear regression models on the absolute power from 30 to 45 Hz separately for wake, NREM, and REM stages. We confirmed that the mean spectral slope grows steeper going from wake to NREM to REM sleep. We found that the choice of mastoid referencing scheme modulated the extent to which electromyogenic, or e...