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 ...

There is uncertainty regarding when and which groups of neurons fire synchronously during seizures. While several studies found heterogeneous firing during seizures, others suggested synchronous neuronal firing in the seizure core. We tested whether neuronal activity during seizures is orderly in the direction of the excitatory neuronal connections in the circuit. There are strong excitatory connections laterally within the septotemporally organized lamella and inhibitory trans-lamellar connections in the hippocampus, which allow testing of the connectivity hypothesis. We further tested whether epileptogenesis enhances synchrony and antiseizure drug administration disrupts it. We recorded local field potentials from CA1 pyramidal neurons using a small microelectrode array and kindled rats by a rapid, recurrent hippocampal stimulation protocol. We compared cross-correlation, theta phase synchronization, entropy, and event synchronization. These analyses revealed that the firing pattern was correlated along ...

Acetaldehyde (ACD), the first metabolite of ethanol, is implicated in several of ethanol's actions, including the reinforcing and aversive effects. The neuronal mechanisms underlying ACD's aversive effect, however, are poorly understood. The lateral habenula (LHb), a regulator of midbrain monoaminergic centers, is activated by negative valence events. Although the LHb has been linked to the aversive responses of several abused drugs, including ethanol, little is known about ACD. We, therefore, assessed ACD's action on LHb neurons in rats. The results showed that intraperitoneal injection of ACD increased cFos protein expression within the LHb and that intra-LHb infusion of ACD induced conditioned place aversion in male rats. Furthermore, electrophysiological recording in brain slices of male and female rats showed that bath application of ACD facilitated spontaneous firing and glutamatergic transmission. This effect of ACD was potentiated by an aldehyde dehydrogenase (ALDH) inhibitor, disulfiram (DS), but ...

Blood pressure is precisely controlled by various sensors around the body. The paraventricular nucleus (PVN) is one of the most important regions in the brain for regulating blood pressure. Briefly, PVN magnocellular neurons project to the neurohypophysis and induce the secretion of vasopressin,

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...

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...

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...

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...