Rethinking retrosplenial cortex: Perspectives and predictions.

The last decade has produced exciting new ideas about retrosplenial cortex (RSC) and its role in integrating diverse inputs. Here, we review the diversity in forms of spatial and directional tuning of RSC activity, temporal organization of RSC activity, and features of RSC interconnectivity with other brain structures. We find that RSC anatomy and dynamics are more consistent with roles in multiple sensorimotor and cognitive processes than with any isolated function. However, two more generalized categories of function may best characterize roles for RSC in complex cognitive processes: (1) shifting and relating perspectives for spatial cognition and (2) prediction and error correction for current sensory states with internal representations of the environment. Both functions likely take advantage of RSC's capacity to encode conjunctions among sensory, motor, and spatial mapping information streams. Together, these functions provide the scaffold for intelligent actions, such as navigation, perspective taking, interaction with others, and error detection.

Cognitive Maps: Distortions of the Hippocampal Space Map Define Neighborhoods.

In place of continuous overhead satellite views of an environment, the brain often relies on first-person experiences to estimate spatial relationships between locations. Using new methods, a recent study has found the spatial metric observed in hippocampal activity adapts to encode local environmental terrain.

Fusion in Breast Cancer Histology Classification.

Breast cancer is a deadly disease that affects millions of women worldwide. The International Conference on Image Analysis and Recognition in 2018 presents the BreAst Cancer Histology (ICIAR2018 BACH) image data challenge that calls for computer tools to assist pathologists and doctors in the clinical diagnosis of breast cancer subtypes. Using the BACH dataset, we have developed an image classification pipeline that combines both a shallow learner (support vector machine) and a deep learner (convolutional neural network). The shallow learner and deep learners achieved moderate accuracies of 79% and 81% individually. When being integrated by fusion algorithms, the system outperformed any individual learner with the highest accuracy as 92%. The fusion presents big potential for improving clinical design support.

Bidirectional prefrontal-hippocampal interactions support context-guided memory.

We compared the dynamics of hippocampal and prefrontal interactions in rats as they used spatial contexts to guide the retrieval of object memories. Functional connectivity analysis indicated a flow of contextual information from the hippocampus to prefrontal cortex upon the rat's entry into the spatial context. Conversely, upon the onset of object sampling, the direction of information flow reversed, consistent with prefrontal control over the retrieval of context-appropriate hippocampal memory representations.

Representation of memories in the cortical-hippocampal system: Results from the application of population similarity analyses.

Here we consider the value of neural population analysis as an approach to understanding how information is represented in the hippocampus and cortical areas and how these areas might interact as a brain system to support memory. We argue that models based on sparse coding of different individual features by single neurons in these areas (e.g., place cells, grid cells) are inadequate to capture the complexity of experience represented within this system. By contrast, population analyses of neurons with denser coding and mixed selectivity reveal new and important insights into the organization of memories. Furthermore, comparisons of the organization of information in interconnected areas suggest a model of hippocampal-cortical interactions that mediates the fundamental features of memory.

Type II integral membrane protein, TM of J paramyxovirus promotes cell-to-cell fusion.

Paramyxoviruses include many important animal and human pathogens. Most paramyxoviruses have two integral membrane proteins: fusion protein (F) and attachment proteins hemagglutinin, hemagglutinin-neuraminidase, or glycoprotein (G), which are critical for viral entry into cells. J paramyxovirus (JPV) encodes four integral membrane proteins: F, G, SH, and transmembrane (TM). The function of TM is not known. In this work, we have generated a viable JPV lacking TM (JPV∆TM). JPV∆TM formed opaque plaques compared with JPV. Quantitative syncytia assays showed that JPV∆TM was defective in promoting cell-to-cell fusion (i.e., syncytia formation) compared with JPV. Furthermore, cells separately expressing F, G, TM, or F plus G did not form syncytia whereas cells expressing F plus TM formed some syncytia. However, syncytia formation was much greater with coexpression of F, G, and TM. Biochemical analysis indicates that F, G, and TM interact with each other. A small hydrophobic region in the TM ectodomain from amino acid residues 118 to 132, the hydrophobic loop (HL), was important for syncytial promotion, suggesting that the TM HL region plays a critical role in cell-to-cell fusion.

Orbitofrontal cortex encodes memories within value-based schemas and represents contexts that guide memory retrieval.

There are a substantial number of studies showing that the orbitofrontal cortex links events to reward values, whereas the hippocampus links events to the context in which they occur. Here we asked how the orbitofrontal cortex contributes to memory where context determines the reward values associated with events. After rats learned object-reward associations that differed depending on the spatial context in which the objects were presented, neuronal ensembles in orbitofrontal cortex represented distinct value-based schemas, each composed of a systematic organization of the representations of objects in the contexts and positions where they were associated with reward or nonreward. Orbitofrontal ensembles also represent the different spatial contexts that define the mappings of stimuli to actions that lead to reward or nonreward. These findings, combined with observations on complementary memory representation within the hippocampus, suggest mechanisms through which prefrontal cortex and the hippocampus interact in support of context-guided memory.

Distinct hippocampal time cell sequences represent odor memories in immobilized rats.

Previous studies have revealed the existence of hippocampal "time cells," principal neurons in CA1 that fire at specific moments in temporally organized experiences. However, in all these studies, animals were in motion; and so, temporal modulation might be due, at least in part, to concurrent or planned movement through space or self-generated movement (path integration). Here the activity of hippocampal CA1 neurons was recorded in head-fixed and immobile rats while they remembered odor stimuli across a delay period. Many neurons selectively and reliably activated at brief moments during the delay, as confirmed by several analyses of temporal modulation, during a strong ongoing θ rhythm. Furthermore, each odor memory was represented by a temporally organized ensemble of time cells composed mostly of neurons that were unique to each memory and some that fired at the same or different moments among multiple memories. These results indicate that ongoing or intended movement through space is not necessary for temporal representations in the hippocampus, and highlight the potential role of time cells as a mechanism for representing the flow of time in distinct memories.

Single-dose vaccination of a recombinant parainfluenza virus 5 expressing NP from H5N1 virus provides broad immunity against influenza A viruses.

Influenza viruses often evade host immunity via antigenic drift and shift despite previous influenza virus infection and/or vaccination. Vaccines that match circulating virus strains are needed for optimal protection. Development of a universal influenza virus vaccine providing broadly cross-protective immunity will be of great importance. The nucleoprotein (NP) of influenza A virus is highly conserved among all strains of influenza A viruses and has been explored as an antigen for developing a universal influenza virus vaccine. In this work, we generated a recombinant parainfluenza virus 5 (PIV5) containing NP from H5N1 (A/Vietnam/1203/2004), a highly pathogenic avian influenza (HPAI) virus, between HN and L (PIV5-NP-HN/L) and tested its efficacy. PIV5-NP-HN/L induced humoral and T cell responses in mice. A single inoculation of PIV5-NP-HN/L provided complete protection against lethal heterosubtypic H1N1 challenge and 50% protection against lethal H5N1 HPAI virus challenge. To improve efficacy, NP was inserted into different locations within the PIV5 genome. Recombinant PIV5 containing NP between F and SH (PIV5-NP-F/SH) or between SH and HN (PIV5-NP-SH/HN) provided better protection against H5N1 HPAI virus challenge than did PIV5-NP-HN/L. These results suggest that PIV5 expressing NP from H5N1 has the potential to be utilized as a universal influenza virus vaccine.

Recombinant parainfluenza virus 5 expressing hemagglutinin of influenza A virus H5N1 protected mice against lethal highly pathogenic avian influenza virus H5N1 challenge.

A safe and effective vaccine is the best way to prevent large-scale highly pathogenic avian influenza virus (HPAI) H5N1 outbreaks in the human population. The current FDA-approved H5N1 vaccine has serious limitations. A more efficacious H5N1 vaccine is urgently needed. Parainfluenza virus 5 (PIV5), a paramyxovirus, is not known to cause any illness in humans. PIV5 is an attractive vaccine vector. In our studies, a single dose of a live recombinant PIV5 expressing a hemagglutinin (HA) gene of H5N1 (rPIV5-H5) from the H5N1 subtype provided sterilizing immunity against lethal doses of HPAI H5N1 infection in mice. Furthermore, we have examined the effect of insertion of H5N1 HA at different locations within the PIV5 genome on the efficacy of a PIV5-based vaccine. Interestingly, insertion of H5N1 HA between the leader sequence, the de facto promoter of PIV5, and the first viral gene, nucleoprotein (NP), did not lead to a viable virus. Insertion of H5N1 HA between NP and the next gene, V/phosphorprotein (V/P), led to a virus that was defective in growth. We have found that insertion of H5N1 HA at the junction between the small hydrophobic (SH) gene and the hemagglutinin-neuraminidase (HN) gene gave the best immunity against HPAI H5N1 challenge: a dose as low as 1,000 PFU was sufficient to protect against lethal HPAI H5N1 challenge in mice. The work suggests that recombinant PIV5 expressing H5N1 HA has great potential as an HPAI H5N1 vaccine.

NMDA signaling in CA1 mediates selectively the spatial component of episodic memory.

Recent studies focusing on the memory for temporal order have reported that CA1 plays a critical role in the memory for the sequences of events, in addition to its well-described role in spatial navigation. In contrast, CA3 was found to principally contribute to the memory for the association of items with spatial or contextual information in tasks focusing on spatial memory. Other studies have shown that NMDA signaling in the hippocampus is critical to memory performance in studies that have investigated spatial and temporal order memory independently. However, the role of NMDA signaling separately in CA1 and CA3 in memory that combines both spatial and temporal processing demands (episodic memory) has not been examined. Here we investigated the effect of the deletion of the NR1 subunit of the NMDA receptor in CA1 or CA3 on the spatial and the temporal aspects of episodic memory, using a behavioral task that allows for these two aspects of memory to be evaluated distinctly within the same task. Under these conditions, NMDA signaling in CA1 specifically contributes to the spatial aspect of memory function and is not required to support the memory for temporal order of events.

Amygdala lesions selectively impair familiarity in recognition memory.

A major controversy in the study of memory concerns whether there are distinct medial temporal lobe (MTL) substrates of recollection and familiarity. Studies using receiver operating characteristics analyses of recognition memory indicate that the hippocampus is essential for recollection, but not for familiarity. We found the converse pattern in the amygdala, wherein damage impaired familiarity while sparing recollection. Combined with previous findings, these results dissociate recollection and familiarity by selective MTL damage.