Nicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs), which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes is unknown. ChIs represent less than 1% of the accumbens neuronal population and are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine-seeking behavior. Using chemogenetics in transgenic rats expressing Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bidirectionally manipulated before cue-induced reinstatement. Following nicotine self-administration and extinction, ChIs were activated or inhibited before a cue reinstatement s...

A hallmark of human thought is the ability to think about not just the actual world but also about alternative ways the world could be. One way to study this contrast is through language. Language has grammatical devices for expressing possibilities and necessities, such as the words might or must . With these devices, called “modal expressions,” we can study the actual versus possible contrast in a highly controlled way. While factual utterances such as “There is a monster under my bed” update the here-and-now of a discourse model, a modal version of this sentence, “There might be a monster under my bed,” displaces from the here-and-now and merely postulates a possibility. We used magnetoencephalography (MEG) to test whether the processes of discourse updating and modal displacement dissociate in the brain. Factual and modal utterances were embedded in short narratives, and across two experiments, factual expressions increased the measured activity over modal expressions. However, the localization of the ...

Attentional selection is a function that allocates the brain’s computational resources to the most important part of a visual scene at a specific moment. Saliency map models have been proposed as computational models to predict attentional selection within a spatial location. Recent saliency map models based on deep convolutional neural networks (DCNNs) exhibit the highest performance for predicting the location of attentional selection and human gaze, which reflect overt attention. Trained DCNNs potentially provide insight into the perceptual mechanisms of biological visual systems. However, the relationship between artificial and neural representations used for determining attentional selection and gaze location remains unknown. To understand the mechanism underlying saliency map models based on DCNNs and the neural system of attentional selection, we investigated the correspondence between layers of a DCNN saliency map model and monkey visual areas for natural image representations. We compared the char...

The development of deep convolutional neural networks (CNNs) has recently led to great successes in computer vision, and CNNs have become de facto computational models of vision. However, a growing body of work suggests that they exhibit critical limitations on tasks beyond image categorization. Here, we study one such fundamental limitation, concerning the judgment of whether two simultaneously presented items are the same or different (SD) compared with a baseline assessment of their spatial relationship (SR). In both human subjects and artificial neural networks, we test the prediction that SD tasks recruit additional cortical mechanisms which underlie critical aspects of visual cognition that are not explained by current computational models. We thus recorded electroencephalography (EEG) signals from human participants engaged in the same tasks as the computational models. Importantly, in humans the two tasks were matched in terms of difficulty by an adaptive psychometric procedure; yet, on top of a mo...

A key aspect of behavioral inhibition is the ability to wait before acting. Failures in this form of inhibition result in impulsivity and are commonly observed in various neuropsychiatric disorders. Prior evidence has implicated medial frontal cortex, motor cortex, orbitofrontal cortex (OFC), and ventral striatum in various aspects of inhibition. Here, using distributed recordings of brain activity [with local-field potentials (LFPs)] in rodents, we identified oscillatory patterns of activity linked with action and inhibition. Low-frequency (δ) activity within motor and premotor circuits was observed in two distinct networks, the first involved in cued, sensory-based responses and the second more generally in both cued and delayed actions. By contrast, θ activity within prefrontal and premotor regions (medial frontal cortex, OFC, ventral striatum, and premotor cortex) was linked with inhibition. Connectivity at θ frequencies was observed within this network of brain regions. Interestingly, greater connecti...

The WU-Minn Human Connectome Project (HCP) is a publicly-available dataset containing state-of-the-art structural magnetic resonance imaging (MRI), functional MRI (fMRI), and diffusion MRI (dMRI) for over a thousand healthy subjects. While the planned scope of the HCP included an anatomic connectome, resting-state fMRI (rs-fMRI) forms the bulk of the HCP’s current connectomic output. We address this by presenting a full-cortex connectome derived from probabilistic diffusion tractography and organized into the HCP-MMP1.0 atlas. Probabilistic methods and large sample sizes are preferable for whole-connectome mapping as they increase the fidelity of traced low-probability connections. We find that overall, connection strengths are lognormally distributed and decay exponentially with tract length, that connectivity reasonably matches macaque histologic tracing in homologous areas, that contralateral homologs and left-lateralized language areas are hyperconnected, and that hierarchical similarity influences con...

The medial entorhinal cortex (mEC) shows a high degree of spatial tuning, predominantly grid cell activity, which is reliant on robust, dynamic inhibition provided by local interneurons (INs). In fact, feedback inhibitory microcircuits involving fast-spiking parvalbumin (PV) basket cells (BCs) are believed to contribute dominantly to the emergence of grid cell firing in principal cells (PrCs). However, the strength of PV BC-mediated inhibition onto PrCs is not uniform in this region, but high in the dorsal and weak in the ventral mEC. This is in good correlation with divergent grid field sizes, but the underlying morphologic and physiological mechanisms remain unknown. In this study, we examined PV BCs in layer (L)2/3 of the mEC characterizing their intrinsic physiology, morphology and synaptic connectivity in the juvenile rat. We show that while intrinsic physiology and morphology are broadly similar over the dorsoventral axis, PV BCs form more connections onto local PrCs in the dorsal mEC, independent of...

Neuronal synapses contain hundreds of different protein species important for regulating signal transmission. Characterizing differential expression profiles of proteins within synapses in distinct regions of the brain has revealed a high degree of synaptic diversity defined by unique molecular organization. Multiplexed imaging of in vitro rat primary hippocampal culture models at single synapse resolution offers new opportunities for exploring synaptic reorganization in response to chemical and genetic perturbations. Here, we combine 12-color multiplexed fluorescence imaging with quantitative image analysis and machine learning to identify novel synaptic subtypes within excitatory and inhibitory synapses based on the expression profiles of major synaptic components. We characterize differences in the correlated expression of proteins within these subtypes and we examine how the distribution of these synapses is modified following induction of synaptic plasticity. Under chronic suppression of neuronal acti...

The nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are trophic factors required by distinct population of sensory neurons during development of the nervous system. Neurons that fail to receive appropriate trophic support are lost during this period of naturally occurring cell death. In the last decade, our understanding of the signaling pathways regulating neuronal death following NGF deprivation has advanced substantially. However, the signaling mechanisms promoting BDNF deprivation-induced sensory neuron degeneration are largely unknown. Using a well-established in vitro culture model of dorsal root ganglion (DRG), we have examined degeneration mechanisms triggered on BDNF withdrawal in sensory neurons. Our results indicate differences and similarities between the molecular signaling pathways behind NGF and BDNF deprivation-induced death. For instance, we observed that the inhibition of Trk receptors (K252a), PKC (Gö6976), protein translation (cycloheximide; CHX), or caspases (zVA...

The activity of basal ganglia input receiving motor thalamus (BGMT) makes a critical impact on motor cortical processing, but modification in BGMT processing with Parkinsonian conditions has not be investigated at the cellular level. Such changes may well be expected because of homeostatic regulation of neural excitability in the presence of altered synaptic drive with dopamine depletion. We addressed this question by comparing BGMT properties in brain slice recordings between control and unilaterally 6-hydroxydopamine hydrochloride (6-OHDA)-treated adult mice. At a minimum of one month after 6-OHDA treatment, BGMT neurons showed a highly significant increase in intrinsic excitability, which was primarily because of a decrease in M-type potassium current. BGMT neurons after 6-OHDA treatment also showed an increase in T-type calcium rebound spikes following hyperpolarizing current steps. Biophysical computer modeling of a thalamic neuron demonstrated that an increase in rebound spiking can also be accounted...