The insula contributes to behavioral control and is disrupted by substance abuse, yet we know little about the neural signals underlying these functions or how they are disrupted after chronic drug self-administration. Here, male and female rats self-administered either cocaine (experimental group) or sucrose (control) for 12 consecutive days. After a 1 month withdrawal period, we recorded from insula while rats performed a previously learned reward-guided decision-making task. Cocaine-exposed rats were more sensitive to value manipulations and were faster to respond. These behavioral changes were accompanied by elevated counts of neurons in the insula that increased firing to reward. These neurons also fired more strongly at the start of long-delay trials, when a more immediate reward would be expected, and fired less strongly in anticipation of the actual delivery of delayed rewards. Although reward-related firing to immediate reward was enhanced after cocaine self-administration, reward-predicting cue a...

The neuropeptides CGRP (calcitonin gene-related peptide) and PACAP (pituitary adenylate cyclase-activating polypeptide) have emerged as mediators of migraine, yet the potential overlap of their mechanisms remains unknown. Infusion of PACAP, like CGRP, can cause migraine in people, and both peptides share similar vasodilatory and nociceptive functions. In this study, we have used light aversion in mice as a surrogate for migraine-like photophobia to compare CGRP and PACAP and ask whether CGRP or PACAP actions were dependent on each other. Similar to CGRP, PACAP induced light aversion in outbred CD-1 mice. The light aversion was accompanied by increased resting in the dark, but not anxiety in a light-independent open field assay. Unexpectedly, about one-third of the CD-1 mice did not respond to PACAP, which was not seen with CGRP. The responder and nonresponder phenotypes were stable, inheritable, and not sex linked, although there was a trend for greater responses among male mice. RNA-sequencing analysis of...

Khalid Elsaafien, Matthew K. Kirchner, Mazher Mohammed, Sophia A. Eikenberry, Chloe West, et al. (see pages [4641–4657][1]) The paraventricular nucleus (PVN) of the hypothalamus regulates neuroendocrine and autonomic responses to stress. One group of PVN neurons elicits neuroendocrine responses

Phase-amplitude coupling (PAC), the coupling of the phase of slower electrophysiological oscillations with the amplitude of faster oscillations, is thought to facilitate dynamic integration of neural activity in the brain. Though the brain undergoes dramatic change and development during the first few years of life, how PAC changes through this developmental period has not been extensively studied. Here, we examined PAC through electroencephalography (EEG) data collected during an awake, eyes-open EEG collection paradigm in 98 children between the ages of 3 months and 3 years. We employed non-parametric clustering methods to identify areas of significant PAC across a range of frequency pairs and electrode locations, and examined how PAC strength and phase preference develops in these areas. We found that PAC, primarily between the alpha-beta and gamma frequencies, was positively correlated with age from early infancy to early childhood (p = 2.035 x 10−6). Additionally, we found gamma over anterior electrod...

Large neuroimaging datasets, including information about structural (SC) and functional connectivity (FC), play an increasingly important role in clinical research, where they guide the design of algorithms for automated stratification, diagnosis or prediction. A major obstacle is, however, the problem of missing features (e.g., lack of concurrent DTI SC and resting-state fMRI FC measurements for many of the subjects). We propose here to address the missing connectivity features problem by introducing strategies based on computational whole-brain network modeling. Using two datasets, the ADNI dataset and a healthy aging dataset, for proof-of-concept, we demonstrate the feasibility of virtual data completion (i.e., inferring “virtual FC” from empirical SC or “virtual SC” from empirical FC), by using self-consistent simulations of linear and nonlinear brain network models. Furthermore, by performing machine learning classification (to separate age classes or control from patient subjects) we show that algor...

Understanding adolescent decision-making is significant for informing basic models of neurodevelopment as well as for the domains of public health and criminal justice. System-based theories posit that adolescent decision-making is guided by activity amongst reward and control processes. While successful at explaining behavior, system-based theories have received inconsistent support at the neural level, perhaps because of methodological limitations. Here, we used two complementary approaches to overcome said limitations and rigorously evaluate system-based models. Using decision-level modeling of fMRI data from a risk-taking task in a sample of 2000+ decisions across 51 human adolescents (25 females, mean age = 15.00 years), we find support for system-based theories of decision-making. Neural activity in lateral prefrontal cortex and a multivariate pattern of cognitive control both predicted a reduced likelihood of risk-taking, whereas increased activity in the nucleus accumbens predicted a greater likeli...

Theoretical and modeling studies demonstrate that heterosynaptic plasticity—changes at synapses inactive during induction—facilitates fine-grained discriminative learning in Hebbian-type systems, and helps to achieve a robust ability for repetitive learning. A dearth of tools for selective manipulation has hindered experimental analysis of the proposed role of heterosynaptic plasticity in behavior. Here we circumvent this obstacle by testing specific predictions about the behavioral consequences of the impairment of heterosynaptic plasticity by experimental manipulations to adenosine A1 receptors (A1Rs). Our prior work demonstrated that the blockade of adenosine A1 receptors impairs heterosynaptic plasticity in brain slices and, when implemented in computer models, selectively impairs repetitive learning on sequential tasks. Based on this work, we predict that A1R knock-out (KO) mice will express (1) impairment of heterosynaptic plasticity and (2) behavioral deficits in learning on sequential tasks. Using ...

Early postnatal experience shapes both inhibitory and excitatory networks in the hippocampus. However, the underlying circuit plasticity is unclear. Using an enriched environment (EE) paradigm during the preweaning period in mice of either sex, we assessed the circuit plasticity of inhibitory cell types in the hippocampus. We found that cholecystokinin (CCK)-expressing basket cells strongly increased somatic inhibition on the excitatory granular cells (GCs) following EE, whereas another pivotal inhibitory cell type, parvalbumin (PV)-expressing cells, did not show changes. Using electrophysiological analysis and the use of cannabinoid receptor 1 (CB1R) agonist WIN 55 212–2, we demonstrate that the change in somatic inhibition from CCK+ neurons increases CB1R-mediated inhibition in the circuit. By inhibiting activity of the entorhinal cortex (EC) using a chemogenetic approach, we further demonstrate that the activity of the projections from the EC mediates the developmental assembly of CCK+ basket cell netwo...

Multivariate analyses of hemodynamic signals serve to identify the storage of specific stimulus contents in working memory (WM). Representations of visual stimuli have been demonstrated both in sensory regions and in higher cortical areas. While previous research has typically focused on the WM maintenance of a single content feature, it remains unclear whether two separate features of a single object can be decoded concurrently. Also, much less evidence exists for representations of auditory compared with visual stimulus features. To address these issues, human participants had to memorize both pitch and perceived location of one of two sample sounds. After a delay phase, they were asked to reproduce either pitch or location. At recall, both features showed comparable levels of discriminability. Region of interest (ROI)-based decoding of functional magnetic resonance imaging (fMRI) data during the delay phase revealed feature-selective activity for both pitch and location of a memorized sound in auditory ...

A central challenge in the study of conscious perception lies in dissociating the neural correlates of perceptual awareness from those reflecting its precursors and consequences. No-report paradigms have been instrumental in this endeavor, demonstrating that the event-related potential P300, recorded from the human scalp, reflects reports rather than awareness. However, these paradigms cannot probe the degree to which stimuli are consciously processed from trial to trial and, thus, leave open the possibility that the P300 is a genuine correlate of conscious access enabling reports. Here, instead of removing report requirements, we took the opposite approach and equated postperceptual task demands across conscious and unconscious trials by orthogonalizing target detection and overt reports in a somatosensory detection task. We used Bayesian model selection to track the transformation from physical to perceptual processing stages in the EEG data of 24 male and female participants and show that the early P50 ...