Systemic treatment with resiniferatoxin (RTX) induces small-fiber sensory neuropathy by damaging TRPV1-expressing primary sensory neurons and causes distinct thermal sensory impairment and tactile allodynia, which resemble the unique clinical features of postherpetic neuralgia. However, the synaptic plasticity associated with RTX-induced tactile allodynia remains unknown. In this study, we found that RTX-induced neuropathy is associated with α2δ-1 upregulation in the dorsal root ganglion (DRG) and increased physical interaction between α2δ-1 and GluN1 in the spinal cord synaptosomes. RNAscope in situ hybridization showed that RTX treatment significantly increased α2δ-1 expression in DRG neurons labeled with CGRP, IB4, NF200, and tyrosine hydroxylase. Electrophysiological recordings revealed that RTX treatment augmented the frequency of miniature excitatory postsynaptic currents (mEPSCs) and the amplitude of evoked EPSCs in spinal dorsal horn neurons, and these effects were reversed by blocking of NMDA rece...

N-methyl-D-aspartate receptors (NMDARs) are important for synaptic plasticity associated with many physiological functions and neurological disorders. Protein kinase C (PKC) activation increases the phosphorylation and activity of NMDARs, and α2δ-1 is a critical NMDAR-interacting protein and controls synaptic trafficking of NMDARs. In this study, we determined the relative roles of PKC and α2δ-1 in the control of NMDAR activity. We found that α2δ-1 coexpression significantly increased NMDAR activity in HEK293 cells transfected with GluN1/GluN2A or GluN1/GluN2B. PKC activation with phorbol 12-myristate 13-acetate (PMA) increased receptor activity only in cells coexpressing GluN1/GluN2A and α2δ-1. Remarkably, PKC inhibition with Gӧ6983 abolished α2δ-1 coexpression–induced potentiation of NMDAR activity in cells transfected with GluN1/GluN2A or GluN1/GluN2B. Treatment with PMA increased the α2δ-1–GluN1 interaction and promoted α2δ-1 and GluN1 cell surface trafficking. PMA also significantly increased NMDAR ac...

New information is rarely learned in isolation, instead most of what we experience can be incorporated into or uses previous knowledge networks in some form. Previous knowledge in form of a cognitive map can facilitate knowledge acquisition and will influence how we learn new spatial information. Here, we developed a new spatial navigation task where food locations are learned in a large, gangway maze to test how mice learn a large spatial map over a longer time period – the HexMaze. Analysing performance across sessions as well as on specific trials, we can show simple memory effects as well as multiple effects of previous knowledge of the map accelerating both online learning and performance increases over offline periods when incorporating new information. We could identify three main phases: 1) Learning the initial goal location, 2) faster learning after two weeks when learning a new goal location and then 3) the ability to express one-session learning leading to long-term memory effect after 12 weeks....

Most neuroimaging experiments that investigate how tools and their actions are represented in the brain use visual paradigms where tools or hands are displayed as 2D images and no real movements are performed. These studies discovered selective visual responses in occipitotemporal and parietal cortices for viewing pictures of hands or tools, which are assumed to reflect action processing, but this has rarely been directly investigated. Here, we examined the responses of independently visually defined category-selective brain areas when participants grasped 3D tools ( N  = 20; 9 females). Using real-action fMRI and multivoxel pattern analysis, we found that grasp typicality representations (i.e., whether a tool is grasped appropriately for use) were decodable from hand-selective areas in occipitotemporal and parietal cortices, but not from tool-, object-, or body-selective areas, even if partially overlapping. Importantly, these effects were exclusive for actions with tools, but not for biomechanically matc...

Relapse susceptibility in women with substance use disorders (SUDs) has been linked to the estrogen, 17β-estradiol (E2). Our previous findings in female rats suggest that the influence of E2 on cocaine seeking can be localized to the prelimbic prefrontal cortex (PrL-PFC). Here, we investigated the receptor mechanisms through which E2 regulates the reinstatement of extinguished cocaine seeking. Sexually mature female rats underwent intravenous cocaine self-administration (0.5 mg/inf; 14 × 2 h daily) and extinction, and then were ovariectomized before reinstatement testing. E2 (10 µg/kg, i.p.) alone did not reinstate cocaine seeking, but it potentiated reinstatement when combined with an otherwise subthreshold priming dose of cocaine. A similar effect was observed following intra-PrL-PFC microinfusions of E2 and by systemic or intra-PrL-PFC administration of the estrogen receptor (ER)β agonist, DPN, but not agonists at ERα or the G-protein-coupled ER1 (GPER1). By contrast, E2-potentiated reinstatement was pr...

Cognitive dysfunction is among the hallmark symptoms of Neurofibromatosis 1, and accordingly, loss of the Drosophila melanogaster ortholog of Neurofibromin 1 (dNf1) precipitates associative learning deficits. However, the affected circuitry in the adult CNS remained unclear and the compromised mechanisms debatable. Although the main evolutionarily conserved function attributed to Nf1 is to inactivate Ras, decreased cAMP signaling on its loss has been thought to underlie impaired learning. Using mixed sex populations, we determine that dNf1 loss results in excess GABAergic signaling to the central for associative learning mushroom body (MB) neurons, apparently suppressing learning. dNf1 is necessary and sufficient for learning within these non-MB neurons, as a dAlk and Ras1-dependent, but PKA-independent modulator of GABAergic neurotransmission. Surprisingly, we also uncovered and discuss a postsynaptic Ras1-dependent, but dNf1-independnet signaling within the MBs that apparently responds to presynaptic GAB...

Impairment of episodic memory, a class of memory for spatiotemporal context of an event, is an early symptom of Alzheimer’s disease. Both spatial and temporal information are encoded and represented in the hippocampal neurons, but how these representations are impaired under amyloid β (Aβ) pathology remains elusive. We performed chronic imaging of the hippocampus in awake male amyloid precursor protein ( App ) knock-in mice behaving in a virtual reality environment to simultaneously monitor spatiotemporal representations and the progression of Aβ depositions. We found that temporal representation is preserved, whereas spatial representation is significantly impaired in the App knock-in mice. This is because of the overall reduction of active place cells, but not time cells, and compensatory hyperactivation of remaining place cells near Aβ aggregates. These results indicate the differential impact of Aβ aggregates on two major modalities of episodic memory, suggesting different mechanisms for forming and ma...

Recent work has shown that the brain’s default mode network (DMN) is active when people imagine the future. Here, we test in human participants (both sexes) whether future imagination can be decomposed into two dissociable psychological processes linked to different subcomponents of the DMN. While measuring brain activity with fMRI as subjects imagine future events, we manipulate the vividness of these events to modulate the demands for event construction, and we manipulate the valence of these events to modulate the demands for event evaluation. We found that one subcomponent of the DMN, the ventral DMN or medial temporal lobe (MTL) subsystem, responds to the vividness but not the valence of imagined events. In contrast, another subcomponent, the dorsal or core DMN, responds to the valence but not the vividness of imagined events. This separate modifiability of different subcomponents of the DMN by vividness and valence provides strong evidence for a neurocognitive dissociation between (1) the constructio...

We developed a method for single-cell resolution longitudinal bioluminescence imaging of PERIOD (PER) protein and TIMELESS (TIM) oscillations in cultured male adult Drosophila brains that captures circadian circuit-wide cycling under simulated day/night cycles. Light input analysis confirms that CRYPTOCHROME (CRY) is the primary circadian photoreceptor and mediates clock disruption by constant light (LL), and that eye light input is redundant to CRY; 3-h light phase delays (Friday) followed by 3-h light phase advances (Monday morning) simulate the common practice of staying up later at night on weekends, sleeping in later on weekend days then returning to standard schedule Monday morning [weekend light shift (WLS)]. PER and TIM oscillations are highly synchronous across all major circadian neuronal subgroups in unshifted light schedules for 11 d. In contrast, WLS significantly dampens PER oscillator synchrony and rhythmicity in most circadian neurons during and after exposure. Lateral ventral neuron (LNv) ...