Medial prefrontal lesions impair performance in an operant delayed nonmatch to sample working memory task.

Cognitive functions, such as working memory, are disrupted in most psychiatric disorders. Many of these processes are believed to depend on the medial prefrontal cortex (mPFC). Traditionally, maze-based behavioral tasks, which have a strong exploratory component, have been used to study the role of the mPFC in working memory in mice. In maze tasks, mice navigate through the environment and require a significant amount of time to complete each trial, thereby limiting the number of trials that can be run per day. Here, we show that an operant-based delayed nonmatch to sample (DNMS) working memory task, with shorter trial lengths and a smaller exploratory component, is also mPFC-dependent. We created excitotoxic lesions in the mPFC of mice and found impairments in both the acquisition of the task, with no delay, and in the performance with delays introduced. Importantly, we saw no differences in trial length, reward collection, or lever-press latencies, indicating that the difference in performance was not due to a change in motivation or mobility. Using this operant DNMS task will facilitate the analysis of working memory and improve our understanding of the physiology and circuit mechanisms underlying this cognitive process. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Combined Social and Spatial Coding in a Descending Projection from the Prefrontal Cortex.

Social behaviors are crucial to all mammals. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant or how they contribute. We found that PL contains anatomically and molecularly distinct subpopulations that target three downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), amygdala, and ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased the preference for a social target. To determine what information PL-NAc neurons convey, we selectively recorded from them and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially specific manipulation of these neurons bidirectionally regulated the formation of a social-spatial association. Thus, the unexpected combination of social and spatial information within the PL-NAc may contribute to social behavior by supporting social-spatial learning.

Dissociated sequential activity and stimulus encoding in the dorsomedial striatum during spatial working memory.

Several lines of evidence suggest that the striatum has an important role in spatial working memory. The neural dynamics in the striatum have been described in tasks with short delay periods (1-4 s), but remain largely uncharacterized for tasks with longer delay periods. We collected and analyzed single unit recordings from the dorsomedial striatum of rats performing a spatial working memory task with delays up to 10 s. We found that neurons were activated sequentially, with the sequences spanning the entire delay period. Surprisingly, this sequential activity was dissociated from stimulus encoding activity, which was present in the same neurons, but preferentially appeared towards the onset of the delay period. These observations contrast with descriptions of sequential dynamics during similar tasks in other brains areas, and clarify the contribution of the striatum to spatial working memory.

Reward and choice encoding in terminals of midbrain dopamine neurons depends on striatal target.

Dopaminergic (DA) neurons in the midbrain provide rich topographic innervation of the striatum and are central to learning and to generating actions. Despite the importance of this DA innervation, it remains unclear whether and how DA neurons are specialized on the basis of the location of their striatal target. Thus, we sought to compare the function of subpopulations of DA neurons that target distinct striatal subregions in the context of an instrumental reversal learning task. We identified key differences in the encoding of reward and choice in dopamine terminals in dorsal versus ventral striatum: DA terminals in ventral striatum responded more strongly to reward consumption and reward-predicting cues, whereas DA terminals in dorsomedial striatum responded more strongly to contralateral choices. In both cases the terminals encoded a reward prediction error. Our results suggest that the DA modulation of the striatum is spatially organized to support the specialized function of the targeted subregion.

A systems approach to hemostasis: 4. How hemostatic thrombi limit the loss of plasma-borne molecules from the microvasculature.

Previous studies have shown that hemostatic thrombi formed in response to penetrating injuries have a core of densely packed, fibrin-associated platelets overlaid by a shell of less-activated, loosely packed platelets. Here we asked, first, how the diverse elements of this structure combine to stem the loss of plasma-borne molecules and, second, whether antiplatelet agents and anticoagulants that perturb thrombus structure affect the re-establishment of a tight vascular seal. The studies combined high-resolution intravital microscopy with a photo-activatable fluorescent albumin marker to simultaneously track thrombus formation and protein transport following injuries to mouse cremaster muscle venules. The results show that protein loss persists after red cell loss has ceased. Blocking platelet deposition with an αIIbß3antagonist delays vessel sealing and increases extravascular protein accumulation, as does either inhibiting adenosine 5'-diphosphate (ADP) P2Y12receptors or reducing integrin-dependent signaling and retraction. In contrast, sealing was unaffected by introducing hirudin to block fibrin accumulation or a Gi2α gain-of-function mutation to expand the thrombus shell. Collectively, these observations describe a novel approach for studying vessel sealing after injury in real time in vivo and show that (1) the core/shell architecture previously observed in arterioles also occurs in venules, (2) plasma leakage persists well beyond red cell escape and mature thrombus formation, (3) the most critical events for limiting plasma extravasation are the stable accumulation of platelets, ADP-dependent signaling, and the emergence of a densely packed core, not the accumulation of fibrin, and (4) drugs that affect platelet accumulation and packing can delay vessel sealing, permitting protein escape to continue.