ABSTRACT
Opioid receptors within the CNS regulate pain sensation and mood and are key targets for drugs of abuse. Within the adult rodent hippocampus (HPC), µ-opioid receptor agonists suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting the circuit. However, it is uncertain if this disinhibitory motif is conserved in other cortical regions, species, or across development. We observed that PV-IN mediated inhibition is robustly suppressed by opioids in HPC but not neocortex in mice and nonhuman primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif was established in early development when immature PV-INs and opioids already influence primordial network rhythmogenesis. Acute opioid-mediated modulation was partially occluded with morphine pretreatment, with implications for the effects of opioids on hippocampal network activity during circuit maturation as well as learning and memory. Together, these findings demonstrate that PV-INs exhibit a divergence in opioid sensitivity across brain regions that is remarkably conserved across evolution and highlights the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.
ABSTRACT
As social animals, people are highly sensitive to the attention of others. Seeing someone else gaze at an object automatically draws one's own attention to that object. Monitoring the attention of others aids in reconstructing their emotions, beliefs, and intentions and may play a crucial role in social alignment. Recently, however, it has been suggested that the human brain constructs a predictive model of other people's attention that is far more involved than a moment-by-moment monitoring of gaze direction. The hypothesized model learns the statistical patterns in other people's attention and extrapolates how attention is likely to move. Here, we tested the hypothesis of a predictive model of attention. Subjects saw movies of attention displayed as a bright spot shifting around a scene. Subjects were able to correctly distinguish natural attention sequences (based on eye tracking of prior participants) from altered sequences (e.g., played backward or in a scrambled order). Even when the attention spot moved around a blank background, subjects could distinguish natural from scrambled sequences, suggesting a sensitivity to the spatial-temporal statistics of attention. Subjects also showed an ability to recognize the attention patterns of different individuals. These results suggest that people possess a sophisticated model of the normal statistics of attention and can identify deviations from the model. Monitoring attention is therefore more than simply registering where someone else's eyes are pointing. It involves predictive modeling, which may contribute to our remarkable social ability to predict the mind states and behavior of others.
Subject(s)
Brain , Cognition , Humans , Vision, Ocular , Eye , EmotionsABSTRACT
N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (GRIN1) and two GluN2 subunits (GRIN2A-GRIN2D). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within the GRIN2A gene, which encodes the GluN2A subunit. Here, we show that unlike missense GRIN2A variants, individuals affected with disease-associated null GRIN2A variants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of both Grin2a+/- and Grin2a-/- mice. These alterations in somatic spiking are not due to global upregulation of most Grin genes (including Grin2b). Deeper evaluation of the developing CA1 circuit led us to uncover age- and Grin2a gene dosing-dependent transient delays in the electrophysiological maturation programs of parvalbumin (PV) interneurons. We report that Grin2a+/+ mice reach PV cell electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, with Grin2a+/- mice not reaching PV cell electrophysiological maturation until preadolescence, and Grin2a-/- mice not reaching PV cell electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure susceptibility in disease-associated null GRIN2A patients.
