In temporal lobe epilepsy, interictal spikes (IS)—hyper-synchronous bursts of network activity—occur at high rates in between seizures. We sought to understand the influence of IS on working memory by recording hippocampal local field potentials from male epileptic mice while they performed a delayed alternation task. Interestingly, the rate of IS during behavior did not correlate with performance. Instead, we found that IS were correlated with worse performance when they were spatially non-restricted and occurred during running. In contrast, when IS were clustered at reward locations, animals tended to perform well. A machine learning decoding approach revealed that IS at reward sites were larger than IS elsewhere on the maze, and could be classified as occurring at specific reward locations. Finally, a spiking neural network model revealed that spatially clustered IS preserved hippocampal replay, while spatially dispersed IS disrupted replay by causing over-generalization. Together, these results show that the spatial specificity of IS on the maze, but not rate, correlates with working memory deficits.

Behavioral change studies mostly focus on external reinforcements to modify preferences. Cue-approach training (CAT) is a paradigm that influences preferences by the mere association of stimuli, sensory cues, and a rapid motor response, without external reinforcements. The behavioral effect has been shown to last for months after less than 1 h of training. Here, we used a modified version of CAT by changing the neutral-cue to a number that represented a monetary amount of reward that the participants accumulate (i.e., incentive-cue). After a single training session, we compared behavioral performance and functional connectivity (FC), as measured by resting-state scans using functional magnetic resonance imaging, between two groups (total of 107 males and females in both groups), one receiving a neutral-cue and the other receiving an incentive-cue, at five time points across 1 year. We replicated the maintenance of behavioral changes after 6 months for the nonexternally reinforced neutral-cue participants, but not for the reinforced group. The reinforced training group showed higher FC within the limbic system, whereas the nonexternally reinforced group showed higher functional connectivity within and between default mode and dorsal attention networks. Our findings offer putative neural correlates for both reinforced and nonexternally reinforced preference changes that are maintained over time and which could be implemented in future behavioral change interventions.

The dynamics of social dominance play a significant role in regulating access to resources and influencing reproductive success and survival in nonhuman primates. These dynamics are based on aggressive and submissive interactions that create distinct, hierarchically organized social structures. In humans, whose social behavior is similarly organized, the use of brain imaging based on tractography has identified key neuronal networks of the limbic system underlying social behavior. Among them, the uncinate fasciculus and the cingulum bundle have been associated with aggression and some disorders such as psychopathy. In this study, we have used advanced tractography to study the anatomy of connections underlying social dominance in a colony of 15 female squirrel monkeys (Saimiri sciureus). We correlated the biostructural properties of the uncinate fasciculus and cingulum with behavioral hierarchy measures while controlling for factors such as age, weight, handedness, brain size, and hormonal influences. The fornix, a limbic connection involved in memory, was also included as the control tract. Our findings indicate a significant correlation between the integrity of the right uncinate fasciculus and social dominance measures, including normalized David's scores, aggressive behaviors, and submissive behaviors. Trends observed in the left uncinate fasciculus hint at potential bilateral involvement with a right hemispheric lateralization. These results are consistent with human studies linking the uncinate fasciculus to social aggression and disorders, suggesting an evolutionary continuity in the neuroanatomical substrates of social dominance back to at least 35 million years.

Opioid abuse poses a major healthcare challenge. To meet this challenge, the brain mechanisms underlying opioid abuse need to be more systematically characterized. It is commonly thought that the addictive potential of opioids stems from their ability to enhance the activity of ventral tegmental area (VTA) dopaminergic neurons. Indeed, activation of mu opioid receptors (MORs) disinhibits VTA dopaminergic neurons projecting to the nucleus accumbens, providing a substrate for the rewarding effects of opioids. However, the abuse potential of opioids has also been linked to their ability to suppress pain and aversive states. Although medial VTA dopaminergic neurons are commonly excited by aversive stimuli, the effects of MOR signaling on this circuitry have not been systematically explored. To fill this gap, a combination of anatomical, optogenetic, and electrophysiological approaches were used to study the afferent circuitry of paranigral VTA (pnVTA) dopaminergic neurons and its modulation by MOR signaling in male and female mice. These studies revealed that aversion-linked glutamatergic neurons in the lateral hypothalamus, ventrolateral periaqueductal gray, and lateral habenula innervated a subset of pnVTA dopaminergic neurons and that activation of presynaptic MORs suppressed their ability to drive pnVTA spiking. A distinct set of pnVTA dopaminergic neurons were innervated by lateral hypothalamus GABAergic neurons, which also were subject to MOR modulation. Thus, MORs robustly inhibit the ability of brain circuits coding aversive states to drive the activity of pnVTA dopaminergic neurons, suggesting that the addictive potential of opioids may stem in part from their ability to act as negative reinforcers.

N-Methyl-d-aspartate receptors (NMDARs) play a crucial role in excitatory neurotransmission, with numerous pathogenic variants identified in the GluN subunits, including their ligand-binding domains (LBDs). The prevailing hypothesis postulates that the endoplasmic reticulum (ER) quality control machinery verifies the agonist occupancy of NMDARs, but this was tested in a limited number of studies. Using microscopy and electrophysiology in the human embryonic kidney 293 (HEK293) cells, we found that surface expression of GluN1/GluN2A receptors containing a set of alanine substitutions within the LBDs correlated with the measured EC50 values for glycine (GluN1 subunit mutations) while not correlating with the measured EC50 values for l-glutamate (GluN2A subunit mutations). The mutant cycle of GluN1-S688 residue, including the pathogenic GluN1-S688Y and GluN1-S688P variants, showed a correlation between relative surface expression of the GluN1/GluN2A receptors and the measured EC50 values for glycine, as well as with the calculated ΔGbinding values for glycine obtained from molecular dynamics simulations. In contrast, the mutant cycle of GluN2A-S511 residue did not show any correlation between the relative surface expression of the GluN1/GluN2A receptors and the measured EC50 values for l-glutamate or calculated ΔGbinding values for l-glutamate. Coexpression of both mutated GluN1 and GluN2A subunits led to additive or synergistic alterations in the surface number of GluN1/GluN2A receptors. The synchronized ER release by ARIAD technology confirmed the altered early trafficking of GluN1/GluN2A receptors containing the mutated LBDs. The microscopical analysis from embryonal rat hippocampal neurons (both sexes) corroborated our conclusions from the HEK293 cells.

“Are you talkin’ to me?!” If you ever watched the masterpiece “Taxi Driver” directed by Martin Scorsese, you certainly recall the monologue during which Travis Bickle rehearses an imaginary confrontation in front of a mirror. While remembering this scene, you recollect a myriad of speech features across visual and auditory senses with a smooth sensation of unified memory. The aim of this study was to investigate how the fine-grained synchrony between coinciding visual and auditory features impacts brain oscillations when forming multisensory speech memories. We developed a memory task presenting participants with short synchronous or asynchronous movie clips focused on the face of speakers in real interviews, all the while undergoing magnetoencephalography recording. In the synchronous condition, the natural alignment between visual and auditory onsets was kept intact. In the asynchronous condition, auditory onsets were delayed to present lip movements and speech sounds in antiphase specifically with respect to the theta oscillation synchronizing them in the original movie. Our results first showed that theta oscillations in the neocortex and hippocampus were modulated by the level of synchrony between lip movements and syllables during audiovisual speech perception. Second, theta asynchrony between the lip movements and auditory envelope during audiovisual speech perception reduced the accuracy of subsequent theta oscillation reinstatement during memory recollection. We conclude that neural theta oscillations play a pivotal role in both audiovisual integration and memory replay of speech.

The chemokine CXCL12 is a highly conserved peptide that regulates homeostatic processes in the brain throughout life. Recent work shows that CXCL12 increases dendritic spine density in cortical neurons, which requires activation of CXCL12's receptor CXCR4. This same pathway reverses cortical dendritic spine deficits and cognitive impairment in an animal model of neuroHIV. However, it remained unclear if CXCL12 simply preserved existing spines or also engaged spine plasticity processes that drove network-level adaptations. We therefore tested if CXCL12 could regulate dendritic spine turnover, maturation, clustering, and neuronal network activity in primary rat cortical neurons of either sex using live-cell imaging, confocal microscopy, and multielectrode arrays. Intriguingly, CXCL12-treated neurons formed significantly more new spines than controls, and this outcome was blocked by the CXCR4 antagonist AMD3100. CXCL12 also increased the density of thin spines expressing postsynaptic markers, including postsynaptic density protein 95 (PSD-95), phospho-PSD-95Ser295, and GluA1, and allowed neurons to better maintain synaptic PSD-95 puncta size. Thin spines were modestly closer together after CXCL12 treatment, suggesting a possible effect on anatomical spine clustering. These effects translated to structured network activity, as CXCL12 increased spike frequency within network bursts in multielectrode array cultures. Finally, a targeted knockdown of CXCR4 in inhibitory neurons, which mostly lack dendritic spines, prevented CXCL12 from increasing spine density on excitatory neurons. Overall, our findings suggest CXCL12/CXCR4 signaling engages inhibitory neurons along with multiple aspects of spine dynamics and remodeling to shape how broader neuronal networks function.

Through experience, humans can learn to suppress locations that frequently contain distracting stimuli. However, the neural mechanism underlying learned suppression remains largely unknown. In this study, we combined steady-state visually evoked potentials (SSVEPs) with event-related potentials (ERPs) to investigate the mechanism behind statistically learned spatial suppression. Twenty-four male and female human participants performed a version of the additional singleton search task in which one location contained a distractor stimulus frequently. The search stimuli constantly flickered on-and-off the screen, resulting in steady-state entrainment. Prior to search onset, no differences in the SSVEP response were found, though a post hoc analysis did reveal proactive alpha lateralization. Following search onset, clear evoked differences in both the SSVEP and ERP signals emerged at the suppressed location relative to all other locations. Crucially, the early timing of these evoked modulations suggests that learned distractor suppression occurs at the initial stages of visual processing.

Multiple brain regions need to coordinate activity to support cognitive flexibility and behavioral adaptation. Neural activity in both the hippocampus (HPC) and medial prefrontal cortex (mPFC) is known to represent the spatial context and is sensitive to reward and rule alterations. Midbrain dopamine (DA) activity is key to reward-seeking behavior and learning. There is abundant evidence that midbrain DA modulates HPC and PFC activity. However, it remains underexplored how these networks engage dynamically and coordinate temporally when animals adjust their behavior according to changing reward contingencies. In particular, is there any relationship between DA reward prediction change during rule switching and rule representation changes in mPFC and CA1? We addressed these questions using simultaneous recordings of neuronal population activity from the hippocampal area CA1, mPFC, and ventral tegmental area (VTA) in male TH-Cre rats performing two spatial working memory tasks with frequent rule switches in blocks of trials. CA1 and mPFC ensembles showed rule-specific activity both during maze running and at reward locations, with mPFC rule coding more consistent across animals compared with CA1. Optogenetically tagged VTA DA neuron firing activity responded to and predicted reward outcome. We found that the correct prediction in DA emerged gradually over trials after rule switching in coordination with transitions in mPFC and CA1 ensemble representations of the current rule after a rule switch, followed by behavioral adaptation to the correct rule sequence. Therefore, our study demonstrates a crucial temporal coordination between the rule representation in mPFC/CA1, the dopamine reward signal, and behavioral strategy.