Perineuronal net (PNN) accumulation around parvalbumin-expressing (PV) inhibitory interneurons marks the closure of critical periods of high plasticity, whereas PNN removal reinstates juvenile plasticity in the adult cortex. Using targeted chemogenetic in vivo approaches in the adult mouse visual cortex, we found that transient inhibition of PV interneurons, through metabotropic or ionotropic chemogenetic tools, induced PNN regression. Electroencephalographic recordings indicated that inhibition of PV interneurons did not elicit unbalanced network excitation. Likewise, inhibition of local excitatory neurons also induced PNN regression, whereas chemogenetic excitation of either PV or excitatory neurons did not reduce the PNN. We also observed that chemogenetically inhibited PV interneurons exhibited reduced PNN compared to their untransduced neighbors, and confirmed that single PV interneurons express multiple genes enabling individual regulation of their own PNN density. Our results indicate that PNN densi...

Synapses are actively dismantled to mediate circuit refinement, but the developmental pathways that regulate synaptic disassembly are largely unknown. We have previously shown that the epithelial sodium channel ENaC/UNC-8 triggers an activity-dependent mechanism that drives the removal of presynaptic proteins liprin-α/SYD-2, Synaptobrevin/SNB-1, RAB-3 and Endophilin/UNC-57 in remodeling GABAergic neurons in C. elegans (Miller-Fleming et al., 2016). Here, we report that the conserved transcription factor Iroquois/IRX-1 regulates UNC-8 expression as well as an additional pathway, independent of UNC-8, that functions in parallel to dismantle functional presynaptic terminals. We show that the additional IRX-1-regulated pathway is selectively required for the removal of the presynaptic proteins, Munc13/UNC-13 and ELKS, which normally mediate synaptic vesicle fusion and neurotransmitter release. Our findings are notable because they highlight the key role of transcriptional regulation in synapse elimination duri...

Systemic administration of ML297, a selective activator of G protein-gated inwardly rectifying K+ (GIRK) channels, decreases innate avoidance behavior in male C57BL/6J mice. The cellular mechanisms mediating the ML297-induced suppression of avoidance behavior are unknown. Here, we show that systemic ML297 administration suppresses elevated plus maze (EPM)-induced neuronal activation in the ventral hippocampus (vHPC) and basolateral amygdala (BLA), and that ML297 activates GIRK1-containing GIRK channels in these limbic structures. While intracranial infusion of ML297 into the vHPC suppressed avoidance behavior in the EPM test, mirroring the effect of systemic ML297, intra-BLA administration of ML297 provoked the opposite effect. Using neuron-specific viral genetic and chemogenetic approaches, we found that the combined inhibition of excitatory neurons in CA3 and dentate gyrus (DG) sub-regions of the vHPC was sufficient to decrease innate avoidance behavior in the EPM, open-field, and light-dark tests in mal...

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...

Cholinergic regulation of hippocampal circuit activity has been an active area of neurophysiological research for decades. The prominent cholinergic innervation of intrinsic hippocampal circuitry, potent effects of cholinomimetic drugs, and behavioral responses to cholinergic modulation of hippocampal circuitry have driven investigators to discover diverse cellular actions of acetylcholine in distinct sites within hippocampal circuitry. Further research has illuminated how these actions organize circuit activity to optimize encoding of new information, promote consolidation, and coordinate this with recall of prior memories. The development of the hippocampal slice preparation was a major advance that accelerated knowledge of how hippocampal circuits functioned and how acetylcholine modulated these circuits. Using this preparation in the early 1980s, we made a serendipitous finding of a novel presynaptic inhibitory effect of acetylcholine on Schaffer collaterals, the projections from CA3 pyramidal neurons ...

Astrocytes exist throughout the CNS and affect neural circuits and behavior through intracellular Ca2+ signaling. Studying the function(s) of astrocyte Ca2+ signaling has proven difficult because of the paucity of tools to achieve selective attenuation. Based on recent studies, we generated and used male and female knock-in mice for Cre-dependent expression of mCherry-tagged hPMCA2w/b to attenuate astrocyte Ca2+ signaling in genetically defined cells in vivo (CalExflox mice for Calcium Extrusion). We characterized CalExflox mice following local AAV-Cre microinjections into the striatum and found reduced astrocyte Ca2+ signaling (∼90%) accompanied with repetitive self-grooming behavior. We also crossed CalExflox mice to astrocyte-specific Aldh1l1 -Cre/ERT2 mice to achieve inducible global CNS-wide Ca2+ signaling attenuation. Within 6 d of induction in the bigenic mice, we observed significantly altered ambulation in the open field, disrupted motor coordination and gait, and premature lethality. Furthermore,...

Reactive oxygen species (ROS) produced by NADPH oxidases (Nox) contribute to the development of different types of sensorineural hearing loss (SNHL), a common impairment in humans with no established treatment. Although the essential role of Nox3 in otoconia biosynthesis and its possible involvement in hearing have been reported in rodents, immunohistological methods targeted at detecting Nox3 expression in inner ear cells reveal ambiguous results. Therefore, the mechanism underlying Nox3-dependent SNHL remains unclear and warrants further investigation. We generated Nox3-Cre knock-in mice, in which Nox3 was replaced with Cre recombinase ( Cre ). Using Nox3-Cre;tdTomato mice of either sex, in which tdTomato is expressed under the control of the Nox3 promoter, we determined Nox3-expressing regions and cell types in the inner ear. Nox3-expressing cells in the cochlea included various types of supporting cells, outer hair cells, inner hair cells, and spiral ganglion neurons. Nox3 expression increased with cis...

In the article, “Cross Recruitment of Domain-Selective Cortical Representations Enables Flexible Semantic Knowledge,” by Scott L. Fairhall, which appeared on pages [3096–3103][1] of the April 8, 2020 issue, errors were published. The description of the initial stimulus selection includes

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