Functional Differentiation of Dorsal and Ventral Posterior Parietal Cortex of the Rat: Implications for Controlled and Stimulus-Driven Attention.

The posterior parietal cortex (PPC) is important for visuospatial attention. The primate PPC shows functional differentiation such that dorsal areas are implicated in top-down, controlled attention, and ventral areas are implicated in bottom-up, stimulus-driven attention. Whether the rat PPC also shows such functional differentiation is unknown. Here, we address this open question using functional neuroanatomy and in vivo electrophysiology. Using conventional tract-tracing methods, we examined connectivity with other structures implicated in visuospatial attention including the lateral posterior nucleus of the thalamus (LPn) and the postrhinal cortex (POR). We showed that the LPn projects to the entire PPC, preferentially targeting more ventral areas. All parts of the PPC and POR are reciprocally connected with the strongest connections evident between ventral PPC and caudal POR. Next, we simultaneously recorded neuronal activity in dorsal and ventral PPC as rats performed a visuospatial attention (VSA ) task that engages in both bottom-up and top-down attention. Previously, we provided evidence that the dorsal PPC is engaged in multiple cognitive process including controlled attention (Yang et al. 2017). Here, we further showed that ventral PPC cells respond to stimulus onset more rapidly than dorsal PPC cells, providing evidence for a role in stimulus-driven, bottom-up attention.

Single neuron activity and theta modulation in the posterior parietal cortex in a visuospatial attention task.

The posterior parietal cortex (PPC) is implicated in directing and maintaining visual attention to locations in space. We hypothesized that the PPC also engages other cognitive processes in the transformation of behaviorally relevant visual inputs into appropriate actions, for example, monitoring of multiple locations, selection of responses to locations in space, and monitoring the outcome of response selections. We recorded single cells and local field potentials in the rat PPC during performance on a novel visuospatial attention (VSA) task that requires visually monitoring locations in space in order to make appropriate stimulus-guided locomotor responses. In each trial, rats attended to four locations on the floor of a maze. A randomly chosen location was briefly illuminated. Approach to the correct target location was followed by food reward. We observed that PPC activity correlated with multiple phases of the VSA task, including monitoring for stimulus onset, detection of a target, spatial location of the target, and target choice. A substantial proportion of cells with behavioral correlates were also modulated by outcome of the trial. Our analyses of local field potentials revealed strong oscillatory rhythms in the theta frequency band, and more than a third of PPC neurons were phase locked to theta oscillations. As in other brain regions, theta power correlated with running speed. Peak theta power was higher in superficial layers than deep layers providing evidence against volume conduction from the hippocampus. In addition, theta power was sensitive to the outcome of a choice. Theta power was significantly higher following incorrect choices compared with correct choices, possibly providing a prediction error signal. Our study provides evidence that the rat PPC has multiple roles in the translation of visual information into appropriate behavioral actions. © 2016 Wiley Periodicals, Inc.

Interactions of the dorsal hippocampus, medial prefrontal cortex and nucleus accumbens in formation of fear memory: difference in inhibitory avoidance learning and contextual fear conditioning.

Learning active or reactive responses to fear involves different brain circuitry. This study examined how the nuclus accumbens (NAc), dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) may interact in memory processing for these two kinds of responses. Male Wistar rats with cannulae implanted in these areas were trained on a contextual fear conditioning or inhibitory avoidance task that respectively engaged a reactive or active response to fear in the test. Immediately after training, a memory modulating factor released by stress, norepinephrine (NE), was infused into one region and 4% lidocaine into another to examine if an upstream activation effect could be blocked by the downstream suppression. Retention tested 1 day later showed that in both tasks posttraining infusion of NE at different doses into either the DH or mPFC enhanced retention but the enhancement was blocked by concurrent infusion of lidocaine into the other region, suggesting reliance of the effect on functional integrity of both regions. Further, posttraining intra-NAc lidocaine infusion attenuated memory enhancement of NE infused to the DH or mPFC in the inhibitory avoidance task but did not do so in contextual fear conditioning. These results suggest that NE regulation of memory formation for the reactive and active responses to fear may rely on distinct interactions among the DH, mPFC and NAc.

Pan-Genotypic Direct-Acting Antiviral Agents for Undetermined or Mixed-Genotype Hepatitis C Infection: A Real-World Multi-Center Effectiveness Analysis.

Although the pan-genotypic direct-acting antiviral regimen was approved for treating chronic hepatitis C infection regardless of the hepatitis C virus (HCV) genotype, real-world data on its effectiveness against mixed-genotype or genotype-undetermined HCV infection are scarce. We evaluated the real-world safety and efficacy of two pan-genotypic regimens (Glecaprevir/Pibrentasvir and Sofosbuvir/Velpatasvir) for HCV-infected patients with mixed or undetermined HCV genotypes from the five hospitals in the Changhua Christian Care System that commenced treatment between August 2018 and December 2020. This retrospective study evaluated the efficacy and safety of pan-genotypic direct-acting antiviral (DAA) treatment in adults with HCV infection. The primary endpoint was the sustained virological response (SVR) observed 12 weeks after completing the treatment. Altogether, 2446 HCV-infected patients received the pan-genotypic DAA regimen, 37 (1.5%) patients had mixed-genotype HCV infections and 110 (4.5%) patients had undetermined HCV genotypes. The mean age was 63 years and 55.8% of our participants were males. Nine (6.1%) patients had end-stage renal disease and three (2%) had co-existing hepatomas. We lost one patient to follow-up during treatment and one more patient after treatment. A total of four patients died. However, none of these losses were due to treatment-related side effects. The rates of SVR12 for mixed-genotype and genotype-undetermined infections were 97.1% and 96.2%, respectively, by per-protocol analyses, and 91.9% and 92.7% respectively, by intention-to-treat population analyses. Laboratory adverse events with grades ≥3 included anemia (2.5%), thrombocytopenia (2.5%), and jaundice (0.7%). Pan-genotypic DAAs are effective and well-tolerated for mixed-genotype or genotype-undetermined HCV infection real-world settings.

Running speed and REM sleep control two distinct modes of rapid interhemispheric communication.

Rhythmic gamma-band communication within and across cortical hemispheres is critical for optimal perception, navigation, and memory. Here, using multisite recordings in both rats and mice, we show that even faster ∼140 Hz rhythms are robustly anti-phase across cortical hemispheres, visually resembling splines, the interlocking teeth on mechanical gears. Splines are strongest in superficial granular retrosplenial cortex, a region important for spatial navigation and memory. Spline-frequency interhemispheric communication becomes more coherent and more precisely anti-phase at faster running speeds. Anti-phase splines also demarcate high-activity frames during REM sleep. While splines and associated neuronal spiking are anti-phase across retrosplenial hemispheres during navigation and REM sleep, gamma-rhythmic interhemispheric communication is precisely in-phase. Gamma and splines occur at distinct points of a theta cycle and thus highlight the ability of interhemispheric cortical communication to rapidly switch between in-phase (gamma) and anti-phase (spline) modes within individual theta cycles during both navigation and REM sleep.

Neuronal Activity in the Rat Pulvinar Correlates with Multiple Higher-Order Cognitive Functions.

The pulvinar, also called the lateral posterior nucleus of the thalamus in rodents, is one of the higher-order thalamic relays and the main visual extrageniculate thalamic nucleus in rodents and primates. Although primate studies report the pulvinar is engaged under attentional demands, there are open questions about the detailed role of the pulvinar in visuospatial attention. The pulvinar provides the primary thalamic input to the posterior parietal cortex (PPC). Both the pulvinar and the PPC are known to be important for visuospatial attention. Our previous work showed that neuronal activity in the PPC correlated with multiple phases of a visuospatial attention (VSA) task, including onset of the visual stimuli, decision-making, task-relevant locations, and behavioral outcomes. Here, we hypothesized that the pulvinar, as the major thalamic input to the PPC, is involved in visuospatial attention as well as in other cognitive functions related to the processing of visual information. We recorded the neuronal activity of the pulvinar in rats during their performance on the VSA task. The task was designed to engage goal-directed, top-down attention as well as stimulus-driven, bottom-up attention. Rats monitored three possible locations for the brief appearance of a target stimulus. An approach to the correct target location was followed by a liquid reward. For analysis, each trial was divided into behavioral epochs demarcated by stimulus onset, selection behavior, and approach to reward. We found that neurons in the pulvinar signaled stimulus onset and selection behavior consistent with the interpretation that the pulvinar is engaged in both bottom-up and top-down visuospatial attention. Our results also suggested that pulvinar cells responded to allocentric and egocentric task-relevant locations.

Automated visual cognitive tasks for recording neural activity using a floor projection maze.

Neuropsychological tasks used in primates to investigate mechanisms of learning and memory are typically visually guided cognitive tasks. We have developed visual cognitive tasks for rats using the Floor Projection Maze(1,2) that are optimized for visual abilities of rats permitting stronger comparisons of experimental findings with other species. In order to investigate neural correlates of learning and memory, we have integrated electrophysiological recordings into fully automated cognitive tasks on the Floor Projection Maze(1,2). Behavioral software interfaced with an animal tracking system allows monitoring of the animal's behavior with precise control of image presentation and reward contingencies for better trained animals. Integration with an in vivo electrophysiological recording system enables examination of behavioral correlates of neural activity at selected epochs of a given cognitive task. We describe protocols for a model system that combines automated visual presentation of information to rodents and intracranial reward with electrophysiological approaches. Our model system offers a sophisticated set of tools as a framework for other cognitive tasks to better isolate and identify specific mechanisms contributing to particular cognitive processes.