Protein aggregation can induce explicit neurotoxic events that trigger a number of presently untreatable neurodegenerative disorders. Chaperones, on the other hand, play a neuroprotective role because of their ability to unfold and refold abnormal proteins. The progressive nature of neurotoxic events makes it important to discover endogenous factors that affect pathologic and molecular phenotypes of neurodegeneration in animal models. Here, we identified microtubule-associated protein tau, and chaperones Hsp70 (heat shock protein 70) and DNAJA1 (DJ2) as endogenous substrates of cereblon (CRBN), a substrate-recruiting subunit of cullin4-RING-E3-ligase. This recruitment results in ubiquitin-mediated degradation of tau, Hsp70, and DJ2. Knocking out CRBN enhances the chaperone activity of DJ2, resulting in decreased phosphorylation and aggregation of tau, improved association of tau with microtubules, and reduced accumulation of pathologic tau across brain. Functionally abundant DJ2 could prevent tau aggregati...

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...

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...

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...

We often encounter unexpected events in the environment and must decide on the most appropriate course of action as we react. For example, if a pitcher throws a curveball after throwing fastballs, the batter must rapidly decide whether to swing (action) or to not swing (inhibition). The theory of [

Sevoflurane is widely used in general anesthesia, especially for children. However, prolonged exposure to sevoflurane is reported to be associated with adverse effects on the development of brain in infant monkey. Neural stem cells (NSCs), with potent proliferation, differentiation, and renewing ability, provide an encouraging tool for basic research and clinical therapies for neurodegenerative diseases. We aim to explore the functional effects of injecting NSCs with Phosphodiesterase 7A (PDE7A) knockdown in infant mice exposed to sevoflurane. The effects of PDE7A in NSCs proliferation and differentiation were determined by CCK-8 assay and differentiation-related gene expression assay, respectively. The effects of NSCs with modified PDE7A on mice’s long-term memory and learning ability were assessed by behavioral assays. Our data demonstrated that depleting PDE7A promoted, whereas forcing PDE7A suppressed the activation of cAMP/CREB signaling as well as cell proliferation and neuronal differentiation of NS...

Intercellular adhesion molecule-1 (ICAM-1) promotes adhesion and transmigration of circulating leukocytes across the blood-brain barrier. Traumatic brain injury (TBI) causes transmigrated immunocompetent cells to release mediators (LFA-1 and Mac-1) that stimulate glial and endothelial cells to express ICAM-1 and release cytokines, sustaining neuroinflammation and neurodegeneration. Although a strong correlation exists between TBI-mediated inflammation and impairment in functional outcome following brain trauma, the role of ICAM-1 in impairing functional outcome by inducing neuroinflammation and neurodegeneration after TBI remains inconclusive. The experimental TBI was induced in vivo by fluid percussion injury (10 and 20 psi) in wild-type and ICAM-1-/- mice and in vitro by stretch-injury (3 psi) in brain endothelial cells. We manipulate ICAM-1 pharmacologically and genetically and conducted several biochemical analyses to gain insight into the mechanisms underlying ICAM-1-mediated neuroinflammation and per...

Nitrous oxide (N2O) is a hypnotic gas with anti-depressant and psychedelic properties at subanesthetic concentrations. Despite longstanding clinical use, there is insufficient understanding of its effect on neural dynamics and cortical processing, which is important for mechanistic understanding of its therapeutic effects. We administered subanesthetic (70%), inhaled N2O and studied dynamic changes of spiking rate, spectral content, and somatosensory information representation in primary motor cortex (M1) in two male Rhesus macaques implanted with Utah microelectrode arrays in the hand area of M1. The average, sorted multi-unit spiking rate in M1 increased from 8.1±0.99 to 10.6±1.3 Hz in Monkey W ( p < 0.001) and from 5.6±0.87 to 7.0 ± 1.1 Hz in Monkey N ( p = 0.003). Power spectral densities increased in beta and gamma band power. To evaluate somatosensory content in M1 as a surrogate of information transfer, fingers were lightly brushed and classified using a naïve Bayes classifier. In both monkeys, the ...

Diabetic neuropathic pain (DNP) is a common complication of diabetes characterized by persistent pain. Emerging evidence links astrocytes to mechanical nociceptive processing, and the motor cortex (MCx) is a cerebral cortex region that is known to play a key role in pain regulation. However, the association between MCx astrocytes and DNP pathogenesis remains largely unexplored. Here, we studied this association using designer receptors exclusively activated by designer drugs to specifically manipulate MCx astrocytes. We proved that the selective inhibition of MCx astrocytes reduced DNP in streptozocin (STZ)-induced DNP models and discovered a potential mechanism by which astrocytes release cytokines, including TNF-α and IL-1β, to increase neuronal activation in the MCx, thereby regulating pain. Together, these results demonstrate a pivotal role for MCx astrocytes in DNP pathogenesis and provide new insight into DNP treatment strategies.

The physiological role of the amyloid-precursor protein (APP) is insufficiently understood. Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence exists for a role of APP and its secreted ectodomain APPsα in Hebbian plasticity. Here, we addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue cultures prepared from APP −/− mice of both sexes. In the absence of APP, dentate granule cells failed to strengthen their excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid-β and not by APPsα, and it is neither observed in APP+/+ tissue treated with β- or γ-secretase inhibitors nor in synaptopodin-deficient cultures lacking the Ca2+-dependent molecular machinery of the spine apparatus. Together, these results suggest a role of APP processing via the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of relevance for brain physiology as well as for brain states associated with increas...