Migraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at cortical synapses between pyramidal cells (PCs) and fast-spiking interneurons (FS INs) in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory (E/I) balance in specific circuits is a key pathogenic mechanism. Here, we investigated the cortical layer 2/3 (L2/3) feedback inhibition microcircuit involving somatostatin-expressing (SOM) INs in FHM1 mice of both sexes carrying a gain-of-function mutation in CaV2.1. Unitary inhibitory neurotransmission at SOM IN-PC synapses was unaltered while excitatory neurotransmission at both PC-SOM IN and PC-PC synapses was enhanced, because of increased probability of glutamate release, in FHM1 mice. Short-term s...

Olfactory information is relayed and processed in the olfactory bulb (OB). Mitral cells, the principal output excitatory neurons of the OB, are controlled by multiple types of interneurons. However, mechanisms that regulate the activity of OB interneurons are not well understood. We provide evidence that the transmembrane tyrosine kinase ErbB4 is selectively expressed in subsets of OB inhibitory neurons in both male and female mice. ErbB4-positive (ErbB4+) neurons are mainly located in the glomerular layer (GL) and granule cell layer (GCL) and do not express previously defined markers. Optogenetic activation of GL-ErbB4+ neurons promotes theta oscillation, whereas activation of those in the GCL generates γ oscillations. Stimulation of OB slices with NRG1, a ligand that activates ErbB4, increases GABA transmission onto mitral cells, suggesting a role of OB NRG1-ErbB4 signaling in olfaction. In accord, ErbB4 mutant mice or acute inhibition of ErbB4 by a chemical genetic approach diminishes GABA transmission,...

Large glutamatergic, somatic synapses mediate temporally precise information transfer. In the ventral nucleus of the lateral lemniscus, an auditory brainstem nucleus, the signal of an excitatory large somatic synapse is sign inverted to generate rapid feedforward inhibition with high temporal acuity at sound onsets, a mechanism involved in the suppression of spurious frequency information. The mechanisms of the synaptically driven input–output functions in the ventral nucleus of the lateral lemniscus are not fully resolved. Here, we show in Mongolian gerbils of both sexes that, for stimulation frequencies up to 200 Hz, the EPSC kinetics together with short-term plasticity allow for faithful transmission with only a small increase in latency. Glutamatergic currents are exclusively mediated by AMPARs and NMDARs. Short-term plasticity is frequency-dependent and composed of an initial facilitation followed by depression. Physiologically relevant output generation is limited by the decrease in synaptic conducta...

To understand language, we must infer structured meanings from real-time auditory or visual signals. Researchers have long focused on word-by-word structure building in working memory as a mechanism that might enable this feat. However, some have argued that language processing does not typically involve rich word-by-word structure building, and/or that apparent working memory effects are underlyingly driven by surprisal (how predictable a word is in context). Consistent with this alternative, some recent behavioral studies of naturalistic language processing that control for surprisal have not shown clear working memory effects. In this fMRI study, we investigate a range of theory-driven predictors of word-by-word working memory demand during naturalistic language comprehension in humans of both sexes under rigorous surprisal controls. In addition, we address a related debate about whether the working memory mechanisms involved in language comprehension are language-specialized or domain-general. To do so...

The nucleus accumbens shell (NAcSh) is a key brain region where environmental cues acquire incentive salience to reinforce motivated behaviors. Principal medium spiny neurons (MSNs) in the NAcSh receive extensive glutamatergic projections from limbic regions, among which, the ventral hippocampus (vH) transmits information enriched in contextual cues, and the basolateral amygdala (BLA) encodes real-time arousing states. The vH and BLA project convergently to NAcSh MSNs, both activated in a time-locked manner on a cue-conditioned motivational action. In brain slices prepared from male and female mice, we show that co-activation of the two projections induces long-term potentiation (LTP) at vH-to-NAcSh synapses without affecting BLA-to-NAcSh synapses, revealing a heterosynaptic mechanism through which BLA signals persistently increase the temporally contingent vH-to-NAcSh transmission. Furthermore, this LTP is more prominent in dopamine D1 receptor-expressing (D1) MSNs than D2 MSNs and can be prevented by inh...

Hippo campal impairments are reliably associated with post-traumatic stress disorder (PTSD); however, little research has characterized how increased threat sensitivity may interact with arousal responses to alter hippocampal reactivity, and further how these interactions relate to the sequelae of trauma-related symptoms. In a sample of individuals recently exposed to trauma ( N = 116, 76 female), we found that PTSD symptoms at 2 weeks were associated with decreased hippocampal responses to threat as assessed with fMRI. Further, the relationship between hippocampal threat sensitivity and PTSD symptomology only emerged in individuals who showed transient, high threat-related arousal, as assayed by an independently collected measure of fear potentiated startle. Collectively, our finding suggests that development of PTSD is associated with threat-related decreases in hippocampal function because of increases in fear-potentiated arousal. SIGNIFICANCE STATEMENT Alterations in hippocampal function linked to thr...

Active forgetting occurs in many species, but how behavioral control mechanisms influence which memories are forgotten remains unknown. We previously found that when rats need to retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, this retrieval-induced forgetting relies on prefrontal control processes. Dopaminergic input to the prefrontal cortex is important for executive functions and cognitive flexibility. We found that, in a similar way, retrieval-induced forgetting of competing memories in male rats requires prefrontal dopamine signaling through D1 receptors. Blockade of medial prefrontal cortex D1 receptors as animals encountered a familiar object impaired active forgetting of competing object memories as measured on a later long-term memory test. Inactivation of the ventral tegmental area produced the same pattern of behavior, a pattern that could be reversed by concomitant activation of prefrontal D1 receptors. ...

Schwann cells play a critical role after peripheral nerve injury by clearing myelin debris, forming axon-guiding bands of Büngner, and remyelinating regenerating axons. Schwann cells undergo epigenomic remodeling to differentiate into a repair state that expresses unique genes, some of which are not expressed at other stages of Schwann cell development. We previously identified a set of enhancers that are activated in Schwann cells after nerve injury, and we determined whether these enhancers are preprogrammed into the Schwann cell epigenome as poised enhancers before injury. Poised enhancers share many attributes of active enhancers, such as open chromatin, but are marked by repressive histone H3 lysine 27 (H3K27) trimethylation rather than H3K27 acetylation. We find that most injury-induced enhancers are not marked as poised enhancers before injury indicating that injury-induced enhancers are not preprogrammed in the Schwann cell epigenome. Injury-induced enhancers are enriched with AP-1 binding motifs, ...

The brain encodes and stores information by creating neuronal ensembles. These ensembles can be formed through long-term potentiation (LTP) of synapses between coactivated neurons. Because inhibitory interneurons suppress the activity of other neurons, they can regulate LTP induction by limiting