Deactivation of G protein-coupled receptors (GPCRs) involves multiple phosphorylations followed by arrestin binding, which uncouples the GPCR from G protein activation. Some GPCRs, such as rhodopsin, are reused many times. Arrestin dissociation and GPCR dephosphorylation are key steps in the recycling process. In vitro evidence suggests that visual arrestin (Arr1) binding to light-activated, phosphorylated rhodopsin hinders dephosphorylation. Whether Arr1 binding also affects rhodopsin dephosphorylation in vivo is not known. We investigated this using both male and female mice lacking Arr1. Mice were exposed to bright light and placed in darkness for different periods of time, and differently phosphorylated species of rhodopsin were assayed by isoelectric focusing. For wildtype mice, rhodopsin dephosphorylation was nearly complete by one hour in darkness. Surprisingly, we observed that in the ARR1 knockout rods, rhodopsin remained phosphorylated even after three hours. Delayed dephosphorylation in ARR1 kno...

Electrocorticography (ECoG) methodologically bridges basic neuroscience and understanding of human brains in health and disease. However, the localization of ECoG signals across the surface of the brain and the spatial distribution of their generating neuronal sources are poorly understood. To address this gap, we recorded from rat auditory cortex using customized μECoG, and simulated cortical surface electrical potentials with a full-scale, biophysically detailed cortical column model. Experimentally, μECoG-derived auditory representations were tonotopically organized and signals were anisotropically localized to ≤±200 μm, i.e., a single cortical column. Biophysical simulations reproduce experimental findings, and indicate that neurons in cortical layers V and VI contribute ∼85% of evoked high-gamma signal recorded at the surface. Cell number and synchrony were the primary biophysical properties determining laminar contributions to evoked μECoG signals, while distance was only a minimal factor. Thus, evok...

In order to successfully forage in an environment filled with rewards and threats, animals need to rely on familiar structures of their environment that signal food availability. The central amygdala (CeA) is known to mediate a panoply of consummatory and defensive behaviors, yet how specific activity patterns within CeA subpopulations guide optimal choices is not completely understood. In a paradigm of appetitive conditioning in which mice freely forage for food across a continuum of cues, we found that two major subpopulations of CeA neurons, Somatostatin-positive (CeASst) and protein kinase Cδ-positive (CeAPKCδ) neurons can assign motivational properties to environmental cues. While the proportion of food responsive cells was higher within CeASst than CeAPKCδ neurons, only the activities of CeAPKCδ, but not CeASst, neurons were required for learning of contextual food cues. Our findings point to a model in which CeAPKCδ neurons may incorporate stimulus salience together with sensory features of the envi...

We previously reported that a-disintegrin and metalloproteinase (ADAM)17 is a key protease regulating myelin formation. We now describe a role for ADAM17 during the Wallerian degeneration (WD) process. Unexpectedly, we observed that glial ADAM17, by regulating p75NTR processing, cell autonomously promotes remyelination, while neuronal ADAM17 is dispensable. Accordingly, p75NTR abnormally accumulates specifically when ADAM17 is maximally expressed leading to a downregulation of tissue plasminogen activator (tPA) expression, excessive fibrin accumulation over time, and delayed remyelination. Mutant mice also present impaired macrophage recruitment and defective nerve conduction velocity (NCV). Thus, ADAM17 expressed in Schwann cells, controls the whole WD process, and its absence hampers effective nerve repair. Collectively, we describe a previously uncharacterized role for glial ADAM17 during nerve regeneration. Based on the results of our study, we posit that, unlike development, glial ADAM17 promotes remy...

Tuberous sclerosis complex (TSC) is caused by mutations in Tsc1 or Tsc2 , whose gene products inhibit the small G-protein Rheb1. Rheb1 activates mTORC1, which may cause refractory epilepsy, intellectual disability, and autism. The mTORC1 inhibitors have been used for TSC patients with intractable epilepsy. However, its effectiveness for cognitive symptoms remains unclear. We found a new signaling pathway for synapse formation through Rheb1 activation, but not mTORC1. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib increased unfarnesylated (inactive) Rheb1 levels and restored synaptic abnormalities in cultured Tsc2 +/− neurons, whereas rapamycin did not enhance spine synapse formation. Lonafarnib treatment also restored the plasticity-related Arc (activity-regulated cytoskeleton-associated protein) expression in cultured Tsc2 +/− neurons. Lonafarnib action was partly dependent on the Rheb1 reduction with syntenin. Oral administration of lonafarnib increased unfarnesylated prot...

Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurologic sequelae and is linked to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury model that induces progressive cognitive impairment in males and anxiety in females in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single-nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis and evidence for disrupted ligand-receptor signaling networks in injured mice. Western blot analysis of isolated neurons showed evidence of inflammasome activation and downstream IL-1β processing, as previously demonstrated in acute CNS injury models, and accumulation of misfolded, hyperphos...

Abnormal levels of acoustic activity can result in hearing problems such as tinnitus and language processing disorders, but the underlying cellular and synaptic changes triggered by abnormal activity are not well understood. To address this issue, we studied the time course of activity-dependent changes that occur at auditory nerve synapses in mice of both sexes after noise exposure and conductive hearing loss. We found that EPSC amplitude and synaptic depression decreased within 2 d of noise exposure through a decrease in the probability of vesicle release ( P r). This was followed by a gradual increase in EPSC amplitude through a larger pool of releasable vesicles ( N ). Occlusion of the ear canal led to a rapid decrease in EPSC amplitude through a decrease in N , which was followed by an increase in EPSC amplitude and synaptic depression through an increase in P r. After returning to normal sound levels, synaptic depression recovered to control levels within 1–2 d. However, repeated exposure to noise fo...

Anastasis is a recently described process in which cells recover after late-stage apoptosis activation. The functional consequences of anastasis for cells and tissues are not clearly understood. Using Drosophila , rat and human cells and tissues, including analyses of both males and females, we present evidence that glia undergoing anastasis in the primary astrogliopathy Alexander disease subsequently express hallmarks of senescence. These senescent glia promote non-cell autonomous death of neurons by secreting interleukin family cytokines. Our findings demonstrate that anastasis can be dysfunctional in neurologic disease by inducing a toxic senescent population of astroglia. SIGNIFICANCE STATEMENT Under some conditions cells otherwise destined to die can be rescued just before death in a process called anastasis, or “rising from the dead.” The fate and function of cells undergoing a near death experience is not well understood. Here, we find that in models and patient cells from Alexander disease, an imp...

Loneliness is a public health concern with detrimental effects on physical and mental well-being. Given phenotypical overlaps between loneliness and social anxiety (SA), cognitive-behavioral interventions targeting SA might be adopted to reduce loneliness. However, whether SA and loneliness share the same underlying neurocognitive mechanisms is still an elusive question. The current study aimed at investigating to what extent known behavioral and neural correlates of social avoidance in SA are evident in loneliness. We used a prestratified approach involving 42 (21 females) participants with high loneliness (HL) and 40 (20 females) participants with low loneliness (LL) scores. During fMRI, participants completed a social gambling task to measure the subjective value of engaging in social situations and responses to social feedback. Univariate and multivariate analyses of behavioral and neural data replicated known task effects. However, although HL participants showed increased SA, loneliness was associate...