The mechanisms underlying accumulation of Alzheimer’s disease (AD)-related tau pathology outside of the medial temporal lobe (MTL) in older adults are unknown but crucial to understanding cognitive decline. A growing body of evidence from human and animal studies strongly implicates neural connectivity in the propagation of tau in humans, but the pathways of neocortical tau spread and its consequences for cognitive function are not well understood. Using resting state fMRI and tau PET imaging from a sample of 97 male and female cognitively normal older adults, we examined MTL structures involved in medial parietal tau accumulation and associations with memory function. Functional connectivity between hippocampus and retrosplenial cortex, a key region of the medial parietal lobe, was associated with tau in medial parietal lobe. By contrast, connectivity between entorhinal and retrosplenial cortices did not correlate with medial parietal lobe tau. Further, greater hippocampal-retrosplenial connectivity was a...

Latent pain sensitization (LS) engages pronociceptive signaling pathways in the dorsal horn that include N-methyl-D-aspartate receptor (NMDAR) → adenylyl cyclase-1 (AC1) → protein kinase A (PKA) and Exchange factor directly activated by cAMP (Epac). To determine whether these pathways operate similarly between males and females or are under the inhibitory control of spinal kappa opioid receptors (KOR), we allowed hyperalgesia to resolve after plantar incision and then blocked KOR with intrathecal administration of LY2456302. LY2456302 reinstated hyperalgesia and facilitated touch-evoked immunoreactivity of phosphorylated extracellular signal-regulated kinase (pERK) in neurons (NeuN) but neither astrocytes (GFAP) nor microglial (Iba1). LY2456302 reinstated hyperalgesia even when administered 13 months later, indicating that chronic postoperative pain vulnerability persists for over a year in a latent state of remission. In both sexes, intrathecal MK-801 (an NMDAR competitive antagonist) prevented LY2456302-...

In the article “S-Nitrosylation of Divalent Metal Transporter 1 Enhances Iron Uptake to Mediate Loss of Dopaminergic Neurons and Motoric Deficit,” by Chao Liu, Cheng-Wu Zhang, Shun Qiang Lo, Seok Ting Ang, Katherine Chee Meng Chew, Dejie Yu, Bing Han Chai, Bobby Tan, Fai Tsang, Yee Kit Tai,

Aging, disease, and trauma can lead to loss of vestibular hair cells and permanent vestibular dysfunction. Previous work showed that, following acute destruction of ∼95% of vestibular hair cells in adult mice, ∼20% regenerate naturally (without exogenous factors) through supporting cell transdifferentiation. There is, however, no evidence for the recovery of vestibular function. To gain insight into the lack of functional recovery, we assessed functional differentiation in regenerated hair cells for up to 15 months, focusing on key stages in stimulus transduction and transmission: hair bundles, voltage-gated conductances, and synaptic contacts. Regenerated hair cells had many features of mature type II vestibular hair cells, including polarized mechanosensitive hair bundles with zone-appropriate stereocilia heights, large voltage-gated potassium currents, basolateral processes, and afferent and efferent synapses. Regeneration failed, however, to recapture the full range of properties of normal populations,...

We recently identified an autism spectrum disorder/intellectual disability (ASD/ID)-related de novo mutation hotspot in the Rac1-activating GEF1 domain of the protein Trio. Trio is a Rho guanine nucleotide exchange factor (RhoGEF) that is essential for glutamatergic synapse function. An ASD/ID-related mutation identified in Trio's GEF1 domain, Trio D1368V, produces a pathologic increase in glutamatergic synaptogenesis, suggesting that Trio is coupled to synaptic regulatory mechanisms that govern glutamatergic synapse formation. However, the molecular mechanisms by which Trio regulates glutamatergic synapses are largely unexplored. Here, using biochemical methods, we identify an interaction between Trio and the synaptogenic protein Neuroligin 1 (NLGN1) in the brain. Molecular biological approaches were then combined with super-resolution dendritic spine imaging and whole-cell voltage-clamp electrophysiology in hippocampal slices from male and female rats to examine the impact ASD/ID-related Trio mutations h...

Current theories of visual consciousness disagree about whether it emerges during early stages of processing in sensory brain regions or later when a widespread frontoparietal network becomes involved. Moreover, disentangling conscious perception from task-related postperceptual processes (e.g., report) and integrating results across different neuroscientific methods remain ongoing challenges. The present study addressed these problems using simultaneous EEG-fMRI and a specific inattentional blindness paradigm with three physically identical phases in female and male human participants. In phase 1, participants performed a distractor task during which line drawings of faces and control stimuli were presented centrally. While some participants spontaneously noticed the faces in phase 1, others remained inattentionally blind. In phase 2, all participants were made aware of the task-irrelevant faces but continued the distractor task. In phase 3, the faces became task-relevant. Bayesian analysis of brain respo...

Rab-interacting molecule (RIM)-binding protein 2 (BP2) is a multidomain protein of the presynaptic active zone (AZ). By binding to RIM, bassoon (Bsn), and voltage-gated Ca2+ channels (CaV), it is considered to be a central organizer of the topography of CaV and release sites of synaptic vesicles (SVs) at the AZ. Here, we used RIM-BP2 knock-out (KO) mice and their wild-type (WT) littermates of either sex to investigate the role of RIM-BP2 at the endbulb of Held synapse of auditory nerve fibers (ANFs) with bushy cells (BCs) of the cochlear nucleus, a fast relay of the auditory pathway with high release probability. Disruption of RIM-BP2 lowered release probability altering short-term plasticity and reduced evoked EPSCs. Analysis of SV pool dynamics during high-frequency train stimulation indicated a reduction of SVs with high release probability but an overall normal size of the readily releasable SV pool (RRP). The Ca2+-dependent fast component of SV replenishment after RRP depletion was slowed. Ultrastruct...

Aversive and rewarding experiences can exert a strong influence on subsequent behavior. While decisions are often supported by the value of single past episodes, most research has focused on the role of well-learned value associations. Recent studies have begun to investigate the influence of reward-associated episodes, but it is unclear whether these results generalize to negative experiences, such as pain. To investigate whether and how the value of previous aversive experiences modulates behavior and brain activity, in our experiments female and male human participants experienced episodes of high or low pain in conjunction with incidental, trial-unique neutral pictures. In an incentive-compatible surprise test phase, we found that participants avoided pain-paired objects. In a separate fMRI experiment, at test, participants exhibited significant pain value memory. Neurally, when participants were re-exposed to pain-paired objects, we found no evidence for reactivation of pain-related patterns in pain-r...

The principal neurons of the striatum, the spiny projection neurons (SPNs), make inhibitory synaptic connections with each other via collaterals of their main axon, forming a local lateral inhibition network. Serotonin, acting via the 5-HT1B receptor, modulates neurotransmitter release from SPN terminals in striatal output nuclei, but the role of 5-HT1B receptors in lateral inhibition among SPNs in the striatum is unknown. Here, we report the effects of 5-HT1B receptor activation on lateral inhibition in the mouse striatum. Whole-cell recordings were made from SPNs in acute brain slices of either sex, while optogenetically activating presynaptic SPNs or fast-spiking interneurons (FSIs). Activation of 5-HT1B receptors significantly reduced the amplitude of IPSCs evoked by optical stimulation of both direct and indirect pathway SPNs. This reduction was blocked by application of a 5-HT1B receptor antagonist. Activation of 5-HT1B receptors did not reduce the amplitude of IPSCs evoked from FSIs. These results s...