Primary cilia exhibit a distinct complement of proteins, including G-protein-coupled receptors (GPCRs) that mediate sensory and developmental signals. The localization of GPCRs to the ciliary membrane involves ciliary localization sequences (CLSs), but it is not known how CLSs might relate to cilium type. Here, we studied the localization of two rhodopsin (RHO)-like GPCRs, somatostatin receptor (SSTR3) and RHO, in three types of cilia, from inner medullary collecting duct (IMCD3) cells, hTERT-RPE1 cells (possessing pocket cilia), and rod photoreceptors (whose cilia grow into elaborate phototransductive outer segments). SSTR3 was localized specifically to all three types of cilia, whereas RHO showed more selectivity for the photoreceptor cilium. Focusing on C-terminal CLSs, we characterized a novel CLS in the SSTR3 C terminus, which was required for the robust ciliary localization of SSTR3. Replacing the C terminus of RHO with this SSTR3 CLS-enhanced ciliary localization, compared with full-length RHO in IM...

Abhishek Chadha, Antonio E. Paniagua, and David S. Williams (see pages [7514–7531][1]) Primary cilia fulfill critical cellular functions—most famously moving fluids past the cell membrane—but they also play key sensory and signal transduction roles, requiring a specific complement of

A key aspect of conceptual knowledge is that it can be flexibly applied at different levels of abstraction, implying a hierarchical organization. It is yet unclear how this hierarchical structure is acquired and represented in the brain. Here we investigate the computations underlying the acquisition and representation of the hierarchical structure of conceptual knowledge in the hippocampal-prefrontal system of 32 human participants (22 females). We assessed the hierarchical nature of learning during a novel tree-like categorization task via computational model comparisons. The winning model allowed to extract and quantify estimates for accumulation and updating of hierarchical compared with single-feature-based concepts from behavior. We find that mPFC tracks accumulation of hierarchical conceptual knowledge over time, and mPFC and hippocampus both support trial-to-trial updating. As a function of those learning parameters, mPFC and hippocampus further show connectivity changes to rostro-lateral PFC, whic...

Emotional memories are better remembered than neutral ones, but the mechanisms leading to this memory bias are not well understood in humans yet. Based on animal research, it is suggested that the memory-enhancing effect of emotion is based on central noradrenergic release, which is triggered by afferent vagal nerve activation. To test the causal link between vagus nerve activation and emotional memory in humans, we applied continuous noninvasive transcutaneous auricular vagus nerve stimulation (taVNS) during exposure to emotional arousing and neutral scenes and tested subsequent, long-term recognition memory after 1 week. We found that taVNS, compared with sham, increased recollection-based memory performance for emotional, but not neutral, material. These findings were complemented by larger recollection-related brain potentials (parietal ERP Old/New effect) during retrieval of emotional scenes encoded under taVNS, compared with sham. Furthermore, brain potentials recorded during encoding also revealed t...

Many decisions, from crossing a busy street to choosing a profession, require integration of discrete sensory events. Previous studies have shown that integrative decision-making favors more reliable stimuli, mimicking statistically optimal integration. It remains unclear, however, whether reliability biases operate even when they lead to suboptimal performance. To address this issue, we asked human observers to reproduce the average motion direction of two suprathreshold coherent motion signals presented successively and with varying levels of reliability, while simultaneously recording whole-brain activity using electroencephalography. By definition, the averaging task should engender equal weighting of the two component motion signals, but instead we found robust behavioral biases in participants' average decisions that favored the more reliable stimulus. Using population-tuning modeling of brain activity we characterized tuning to the average motion direction. In keeping with the behavioral biases, the...

Reward prospect weighs on motor decision processes, enhancing the selection of appropriate actions and the inhibition of others. While many studies have investigated the neuronal basis of reward representations and of cortical control of actions, the neuronal correlates of the influences of reward prospect on motor decisions are less clear. We recorded from the dorsal premotor cortex (PMd) of 2 male macaque monkeys performing a modified version of the Stop-signal (countermanding) task. This task challenges motor decisions by requiring responding to a frequent Go stimulus, but to suppress this response when a rare Stop signal is presented during the reaction time. We unbalanced the motivation to respond or to suppress the response by presenting a cue informing on three different rewards schedules: in one case, Go trials were rewarded more than Stop trials; in another case, Stop trials were rewarded more than Go trials; in the last case, both types of trials were rewarded equally. Monkeys adopted different s...

Peptide neuromodulation has been implicated to shield neuronal activity from acute temperature changes that can otherwise lead to loss of motor control or failure of vital behaviors. However, the cellular actions neuropeptides elicit to support temperature-robust activity remain unknown. Here, we find that peptide neuromodulation restores rhythmic bursting in temperature-compromised central pattern generator (CPG) neurons by counteracting membrane shunt and increasing dendritic electrical spread. We show that acutely rising temperatures reduced spike generation and interrupted ongoing rhythmic motor activity in the crustacean gastric mill CPG. Neuronal release and extrinsic application of Cancer borealis tachykinin-related peptide Ia (CabTRP Ia), a substance-P-related peptide, restored rhythmic activity. Warming led to a significant decrease in membrane resistance and a shunting of the dendritic signals in the main gastric mill CPG neuron. Using a combination of fluorescent calcium imaging and electrophysi...

Previous studies have shown that self-generated stimuli in auditory, visual, and somatosensory domains are attenuated, producing decreased behavioral and neural responses compared to the same stimuli that are externally generated. Yet, whether such attenuation also occurs for higher-level cognitive functions beyond sensorimotor processing remains unknown. In this study, we assessed whether cognitive functions such as numerosity estimations are subject to attenuation in 56 healthy participants (32 women). We designed a task allowing the controlled comparison of numerosity estimations for self (active condition) and externally (passive condition) generated words. Our behavioral results showed a larger underestimation of self- compared to externally-generated words, suggesting that numerosity estimations for self-generated words are attenuated. Moreover, the linear relationship between the reported and actual number of words was stronger for self-generated words, although the ability to track errors about num...

Alzheimer's disease is associated with poor sleep, but the impact of tau and β-amyloid (Aβ) pathology on sleep remains largely unknown. Here, we test the hypothesis that tau and Aβ predict unique impairments in objective and self-perceived human sleep under real-life, free-living conditions. Eighty-nine male and female cognitively healthy older adults received 18F-FTP-tau and 11C-PIB-Aβ PET imaging, 7 nights of sleep actigraphy and questionnaire measures, and neurocognitive assessment. Tau burden, but not Aβ, was associated with markedly worse objective sleep. In contrast, Aβ and tau were associated with worse self-reported sleep quality. Of clinical relevance, Aβ burden predicted a unique perceptual mismatch between objective and subject sleep evaluation, with individuals underestimating their sleep. The magnitude of this mismatch was further predicted by worse executive function. Thus, early-stage tau and Aβ deposition are linked with distinct phenotypes of real-world sleep impairment, one that includes ...