The orbitofrontal cortex (OFC) is a brain region involved in higher-order decision-making. Rodent studies show that cocaine self-administration (CSA) reduces OFC contribution to goal-directed behavior and behavioral strategies to avoid drug intake. This change in OFC function persists for many weeks after cocaine withdrawal, suggesting involvement in the process of addiction. The mechanisms underlying impaired OFC function by cocaine are not well-understood. However, studies implicate altered OFC serotonin (5-HT) function in disrupted cognitive processes during addiction and other psychiatric disorders. Thus, it is hypothesized that cocaine impairment of OFC function involves changes in 5-HT signaling, and previous work shows that 5-HT1A and 5-HT2A receptor-mediated effects on OFC pyramidal neurons (PyNs) are impaired weeks after cocaine withdrawal. However, 5-HT effects on other contributors to OFC circuit function have not been fully investigated, including the parvalbumin-containing, fast-spiking intern...

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...

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...

The ventral pallidum (VP) is the major downstream nucleus of the nucleus accumbens (NAc). Both VP and NAc neurons are responsive to reward-predictive stimuli and are critical drivers of reward-seeking behavior. The cue-evoked excitations and inhibitions of NAc neurons predict the vigor (latency and speed) of the cue-elicited locomotor approach response and encode the animal’s proximity to the movement target, but do not encode more specific movement features such as turn direction. VP neurons also encode certain vigor parameters, but it remains unknown whether they also encode more specific movement features, and whether such encoding could account for vigor encoding. To address these questions, we recorded the firing of neurons in the VP of freely moving male rats performing a discriminative stimulus (DS) task. Similar to NAc neurons, VP neurons’ cue-evoked excitations were correlated with the speed of the upcoming approach movement and the animal’s proximity to the movement target at cue onset. Unlike NA...

In auditory behavioral and EEG experiments, the variability of stimulation solutions, for both software and hardware, adds unnecessary technical constraints. Currently, there is no easy to use, inexpensive, and shareable solution that could improve collaborations and data comparisons across different sites and contexts. This article outlines a system composed by a Raspberry Pi coupled with Python programming and associated with a HifiBerry sound card. We compare its sound performances with those of a wide variety of materials and configurations. This solution achieves the high timing accuracy and sound quality important in auditory cognition experiments, while being simple to use and open source. The present system shows high performances and results along with excellent feedback from users. It is inexpensive, easy to build, share, and improve on. Working with such low-cost, powerful, and collaborative hardware and software tools allows people to create their own specific, adapted, and shareable system tha...

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...

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...

The NMDA receptors are a type of glutamate receptors, which is involved in neuronal function, plasticity and development in the mammalian brain. However, how the NMDA receptors contribute to adult neurogenesis and development of the dentate gyrus is unclear. In this study, we investigate this question by examining a region-specific knock-out mouse line that lacks the NR1 gene, which encodes the essential subunit of the NMDA receptors, in granule cells of the dentate gyrus (DG-NR1KO mice). We found that the survival of newly-generated granule cells, cell proliferation and the size of the granule cell layer are significantly reduced in the dorsal dentate gyrus of adult DG-NR1KO mice. Our results also show a significant reduction in the number of immature neurons and in the volume of the granule cell layer, starting from three weeks of postnatal age. DG-NR1KO mice also showed impairment in the expression of an immediate early gene, Arc, and behavior during the novelty-suppressed feeding and open field test. T...