Nicotine is an addictive substance historically consumed through smoking and more recently through the use of electronic vapor devices. The increasing prevalence and popularity of vaping prompts the need for preclinical rodent models of nicotine vapor exposure and an improved understanding of the impact of vaping on specific brain regions, bodily functions, and behaviors. We used a rodent model of electronic nicotine vapor exposure to examine the cellular and behavioral consequences of acute and repeated vapor exposure. Adult male C57BL/6J mice were exposed to a single 3-h session (acute exposure) or five daily sessions (repeated exposure) of intermittent vapes of 120 mg/ml nicotine in propylene glycol:vegetable glycerol (PG/VG) or PG/VG control. Acute and repeated nicotine vapor exposure did not alter body weight, and both exposure paradigms produced pharmacologically significant serum nicotine and cotinine levels in the 120 mg/ml nicotine group compared with PG/VG controls. Acute exposure to electronic n...

Site-specific genetic and epigenetic targeting of distinct cell populations is a central goal in molecular neuroscience and is crucial to understand the gene regulatory mechanisms that underlie complex phenotypes and behaviors. While recent technological advances have enabled unprecedented control over gene expression, many of these approaches are focused on selected model organisms and/or require labor-intensive customization for different applications. The simplicity and modularity of clustered regularly interspaced short palindromic repeats (CRISPR)-based systems have transformed genome editing and expanded the gene regulatory toolbox. However, there are few available tools for cell-selective CRISPR regulation in neurons. We designed, validated, and optimized CRISPR activation (CRISPRa) and CRISPR interference (CRISPRi) systems for Cre recombinase-dependent gene regulation. Unexpectedly, CRISPRa systems based on a traditional double-floxed inverted open reading frame (DIO) strategy exhibited leaky targe...

Learning in sensorimotor adaptation tasks has been viewed as an implicit learning phenomenon. The implicit process affords recalibration of existing motor skills so that the system can adjust to changes in the body or environment without relearning from scratch. However, recent findings suggest that the implicit process is heavily constrained, calling into question its utility in motor learning and the theoretical framework of sensorimotor adaptation paradigms. These inferences have been based mainly on results from single bouts of training, where explicit compensation strategies, such as explicitly re-aiming the intended movement direction, contribute a significant proportion of adaptive learning. It is possible, however, that the implicit process supersedes explicit compensation strategies over repeated practice sessions. We tested this by dissociating the contributions of explicit re-aiming strategies and the implicit process in human participants over five consecutive days of training. Despite a substa...

Autism spectrum disorder (ASD) is a neurologic condition characterized by alterations in social interaction and communication, and restricted and/or repetitive behaviors. The classical Type II cadherins cadherin-8 (Cdh8, CDH8) and cadherin-11 (Cdh11, CDH11) have been implicated as autism risk gene candidates. To explore the role of cadherins in the etiology of autism, we investigated their expression patterns during mouse brain development and in autism-specific human tissue. In mice, expression of cadherin-8 and cadherin-11 was developmentally regulated and enriched in the cortex, hippocampus, and thalamus/striatum during the peak of dendrite formation and synaptogenesis. Both cadherins were expressed in synaptic compartments but only cadherin-8 associated with the excitatory synaptic marker neuroligin-1. Induced pluripotent stem cell (iPSC)-derived cortical neural precursor cells (NPCs) and cortical organoids generated from individuals with autism showed upregulated CDH8 expression levels, but downregula...

The term “memory strength” generally refers to how well one remembers something. But more precisely it contains multiple modalities, such as how easily, how accurately, how confidently and how vividly we remember it. In human, these modalities of memory strength are dissociable. In this study, we asked whether we can isolate a behavioral component that is dissociable from others in hippocampus-dependent memory tasks in mice, which potentially reflect a modality of memory strength. Using a virus-mediated inducible method, we ablated immature neurons in the dentate gyrus in mice after we trained the mice with hippocampus-dependent memory tasks normally. In memory retrieval tests, these ablated mice initially showed intact performance. However, the ablated mice ceased learned behavior prematurely within a trial compared with control mice. In addition, the ablated mice showed shorter duration of individual episodes of learned behavior. Both affected behavioral measurements point to persistence of learned behav...

New information is rarely learned in isolation; instead, most of what we experience can be incorporated into or uses previous knowledge networks in some form. Previous knowledge in form of a cognitive map can facilitate knowledge acquisition and will influence how we learn new spatial information. Here, we developed a new spatial navigation task where food locations are learned in a large, gangway maze to test how mice learn a large spatial map over a longer time period—the HexMaze. Analyzing performance across sessions as well as on specific trials, we can show simple memory effects as well as multiple effects of previous knowledge of the map accelerating both online learning and performance increases over offline periods when incorporating new information. We could identify the following three main phases: (1) learning the initial goal location; (2) faster learning after 2 weeks when learning a new goal location; and then (3) the ability to express one-session learning, leading to long-term memory effect...

Here, we report the independent discovery and validation of stearoyl-CoA desaturase (SCD) as a modulator of α-synuclein (αSyn)-induced pathology and toxicity in cell-based Parkinson’s disease (PD) models. We identified SCD as top altered gene from transcriptional profiling in primary neurons exogenously expressing αSyn with the amplified familial PD mutation 3K. Thus, we sought to further explore SCD as a therapeutic target in neurodegeneration. We report that SCD inhibitors are toxic to early human and rat neuron cultures while displaying minimal toxicity to late cultures. The fatty acid product of SCD, oleic acid (OLA), fully rescues this toxicity in early cultures, suggesting on-target toxicity. Furthermore, SCD inhibition rescues αSyn 3K-induced toxicity in late primary neurons. We also confirm that SCD inhibitors reduce formation of αSyn accumulations, while OLA increases these accumulations in an αSyn 3K neuroblastoma model. However, we identify a caveat with this model where αSyn 3K levels can be su...

Epilepsy is one of the most common neurologic disorders. Around one third of patients do not respond to current medications. This lack of treatment indicates a need for better understanding of the underlying mechanisms and, importantly, the identification of novel targets for drug manipulation. The fruit fly Drosophila melanogaster has a fast reproduction time, powerful genetics, and facilitates large sample sizes, making it a strong model of seizure mechanisms. To better understand behavioral and physiological phenotypes across major fly seizure genotypes we systematically measured seizure severity and secondary behavioral phenotypes at both the larval and adult stage. Comparison of several seizure-induction methods; specifically electrical, mechanical and heat induction, show that larval electroshock is the most effective at inducing seizures across a wide range of seizure-prone mutants tested. Locomotion in adults and larvae was found to be non-predictive of seizure susceptibility. Recording activity in...

Cross-sectional versus longitudinal comparisons of age-related change have often revealed differing results. In the current study, we used within-subject task-based fMRI to investigate changes in voxel-based activations and behavioral performance across the life span in the Reference Ability Neural Network cohort, at both baseline and 5 year follow-up. We analyzed fMRI data from between 127 and 159 participants (20–80 years) on a battery of tests relating to each of four cognitive reference abilities. We applied a Gaussian age kernel to capture continuous change across the life span using a 5 year sliding window centered on each age in our participant sample, with a subsequent division into young, middle, and old age brackets. This method was applied separately to both cross-sectional approximations of change and real longitudinal changes adopting a comparative approach. We then focused on longitudinal measurements of neural change to identify regions expressing peak changes and fluctuations of sign change...

Pitch is a perceptual attribute enabling perception of melody. There is no consensus regarding the fundamental nature of pitch and its underlying neural code. A stimulus which has received much interest in psychophysical and computational studies is noise with a sharp spectral edge. High-pass (HP) or low-pass (LP) noise gives rise to a pitch near the edge frequency (monaural edge pitch; MEP). The simplicity of this stimulus, combined with its spectral and autocorrelation properties, make it an interesting stimulus to examine spectral versus temporal cues that could underly its pitch. We recorded responses of single auditory nerve (AN) fibers in chinchilla to MEP-stimuli varying in edge frequency. Temporal cues were examined with shuffled autocorrelogram (SAC) analysis. Correspondence between the population’s dominant interspike interval and reported pitch estimates was poor. A fuller analysis of the population interspike interval distribution, which incorporates not only the dominant but all intervals, res...