Subjective uncertainty arises because the estimation of the timing of an event into the future is error prone. This impact of stimulus-bound uncertainty on movement preparation has often been investigated using reaction time tasks where a warning stimulus (WS) predicts the occurrence of a “go” signal. The timing of the “go” signal can be chosen from a particular probability distribution with a given variance or uncertainty. It has been repeatedly shown that reaction times covary with the shape of the used “go” signal distribution. This is interpreted as evidence for temporal preparation. Moreover, the variance of the response time should always increase with the duration of the delay between the WS and the “go” signal. This increasing variance has been interpreted as a consequence of the temporal “blurring” of future events (scalar expectancy). The present paper tested the validity of the temporal “blurring” hypothesis in humans with a simple oculomotor reaction time task where subjective and stimulus-boun...

Rapid saccadic eye movements are used by animals to sample different parts of the visual scene. Previous work has investigated neural correlates of these saccades in visual cortical areas such as V1; however, how saccade-responsive neurons are distributed across visual areas, cell types, and cortical layers has remained unknown. Through analyzing 818 1 h experimental sessions from the Allen Brain Observatory, we present a large-scale analysis of saccadic behaviors in head-fixed mice and their neural correlates. We find that saccade-responsive neurons are present across visual cortex, but their distribution varies considerably by transgenically defined cell type, cortical area, and cortical layer. We also find that saccade-responsive neurons do not exhibit distinct visual response properties from the broader neural population, suggesting that the saccadic responses of these neurons are likely not predominantly visually driven. These results provide insight into the roles played by different cell types withi...

Rod and cone photoreceptors degenerate in inherited and age-related retinal degenerative diseases, ultimately leading to loss of vision. Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have shown a link between TH signaling and retinal degeneration. This work investigates the effects of excessive TH signaling on photoreceptor function and survival in mice. C57BL/6, Thra1 −/−, Thrb2 −/−, Thrb −/−, and the cone dominant Nrl −/− mice received triiodothyronine (T3) treatment (5–20 μg/ml in drinking water) for 30 d, followed by evaluations of retinal function, photoreceptor survival/death, and retinal stress/damage. Treatment with T3 reduced light responses of rods and cones by 50–60%, compared with untreated controls. Outer nuclear layer thickness and cone density were reduced by ∼18% and 75%, respectively, after T3 treatment. Retinal sections prepared from T3-treated mice showed significantly increased numbers of TUNEL-positive, p-γH2AX-positive, an...

Drive from peripheral neurons is essential in almost all pain states, but pharmacological silencing of these neurons to effect analgesia has proved problematic. Reversible gene therapy using long-lived chemogenetic approaches is an appealing option. We used the genetically activated chloride channel PSAM4-GlyR to examine pain pathways in mice. Using recombinant AAV9-based delivery to sensory neurons, we found a reversal of acute pain behavior and diminished neuronal activity using in vitro and in vivo GCaMP imaging on activation of PSAM4-GlyR with varenicline. A significant reduction in inflammatory heat hyperalgesia and oxaliplatin-induced cold allodynia was also observed. Importantly, there was no impairment of motor coordination, but innocuous von Frey sensation was inhibited. We generated a transgenic mouse that expresses a CAG-driven FLExed PSAM4-GlyR downstream of the Rosa26 locus that requires Cre recombinase to enable the expression of PSAM4-GlyR and tdTomato. We used NaV1.8 Cre to examine the role...

The sucrose preference test (SPT) is a widely used preclinical assay for studying stress-sensitive reward behaviors and antidepressant treatments in rodents, with some face, construct, and predictive validity. However, while stress-induced loss of sucrose preference is presumed to reflect an anhedonic-like state, little detail is known about what behavioral components may influence performance in the SPT in stress-naive or stressed rodents. We analyzed the licking microstructure of mice during the SPT to evaluate how preference is expressed and lost following chronic stress. In stress-naive mice, preference is expressed as both longer and more numerous drinking bouts at the sucrose bottle, compared with the water bottle. We also found evidence that memory of the sucrose bottle location supports preference. Through manipulations of the caloric content of the sweetener or caloric need of the mouse, we found that energy demands and satiety signals do not affect either preference or the underlying drinking beh...

Dopamine receptor type 2-expressing medium spiny neurons (D2-MSNs) in the medial part of the ventral striatum (VS) induce non-REM (NREM) sleep from the wake state in animals. However, it is unclear whether D2-MSNs in the lateral part of the VS (VLS), which is anatomically and functionally different from the medial part of the VS, contribute to sleep-wake regulation. This study aims to clarify whether and how D2-MSNs in the VLS are involved in sleep-wake regulation. Our study found that specifically removing D2-MSNs in the VLS led to an increase in wakefulness time in mice during the dark phase using a diphtheria toxin-mediated cell ablation/dysfunction technique. D2-MSN ablation throughout the VS further increased dark phase wakefulness time. These findings suggest that VLS D2-MSNs may induce sleep during the dark phase with the medial part of the VS. Next, our fiber photometric recordings revealed that the population intracellular calcium (Ca2+) signal in the VLS D2-MSNs increased during the transition fr...

Behavioral strategies are often classified based on whether reinforcer value controls reinforcement. Value-sensitive behaviors, in which animals update their actions when reinforcer value is changed, are classified as goal-directed; conversely, value-insensitive actions, where behavior remains consistent when the reinforcer is removed or devalued, are considered habitual. Basic reinforcement schedules can help to bias behavior toward either process: random ratio (RR) schedules are thought to promote the formation of goal-directed behaviors while random intervals (RIs) promote habitual control. However, how the schedule-specific features of these tasks interact with other factors that influence learning to control behavior has not been well characterized. Using male and female mice, we asked how distinct food restriction levels, a strategy often used to increase task engagement, interact with RR and RI schedules to control performance during task acquisition and devaluation procedures. We determined that fo...

Drug-induced taste disorders reduce quality of life, but little is known about the molecular mechanisms by which drugs induce taste disturbances. In this study, we investigated the short-term and long-term effects of the antiarrhythmic drug flecainide, which is known to cause taste dysfunction. Analyses of behavioral responses (licking tests) revealed that mice given a single intraperitoneal injection of flecainide exhibited a significant reduction in preference for a sour tastant (HCl) but not for other taste solutions (NaCl, quinine, sucrose, KCl and monopotassium glutamate) when compared with controls. Mice administered a single dose of flecainide also had significantly higher taste nerve responses to HCl but not to other taste solutions. Compared with controls, mice administered flecainide once-daily for 30 d showed a reduced preference for HCl without any changes in the behavioral responses to other taste solutions. The electrophysiological experiments using HEK293T cells transiently expressing otopet...

Chemical fixation using paraformaldehyde (PFA) is a standard step for preserving cells and tissues for subsequent microscopic analyses such as immunofluorescence or electron microscopy (EM). However, chemical fixation may introduce physical alterations in the spatial arrangement of cellular proteins, organelles, and membranes. With the increasing use of super-resolution microscopy to visualize cellular structures with nanometric precision, assessing potential artifacts, and knowing how to avoid them, takes on special urgency. We addressed this issue by taking advantage of live-cell super-resolution microscopy that makes it possible to directly observe the acute effects of PFA on organotypic hippocampal brain slices, allowing us to compare tissue integrity in a “before-and-after” experiment. We applied super-resolution shadow imaging (SUSHI) to assess the structure of the extracellular space (ECS) and regular super-resolution microscopy of fluorescently labeled neurons and astrocytes to quantify key neuroan...

Subjective uncertainty arises because the estimation of the timing of an event into the future is error prone. This impact of stimulus-bound uncertainty on movement preparation has often been investigated using reaction time tasks where a warning stimulus (WS) predicts the occurrence of a ‘go’ signal. The timing of the ‘go’ signal can be chosen from a particular probability distribution with a given variance or uncertainty. It has been repeatedly shown that reaction times covary with the shape of the used ‘go’ signal distribution. This is interpreted as evidence for temporal preparation. Moreover, the variance of the response time should always increase with the duration of the delay between the WS and the ‘go’ signal. This increasing variance has been interpreted as a consequence of the temporal ‘blurring’ of future events (scalar expectancy). The present paper tested the validity of the temporal ‘blurring’ hypothesis in humans with a simple oculomotor reaction time task where subjective and stimulus-bou...