Activity In Retrosplenial Cortex Research Articles

The truth is in there: Belief processes in the human brain.

Belief, defined by William James as the mental state or function of cognizing reality, is a core psychological function with strong influence on emotion and behavior. Furthermore, strong and aberrant beliefs about the world and oneself play important roles in mental disorders. The underlying processes of belief have been the matter of a long debate in philosophy and psychology, and modern neuroimaging techniques can provide insight into the underlying neural processes. Here, we conducted a functional magnetic resonance imaging study with N = 30 healthy participants in which we presented statements about facts, politics, religion, conspiracy theories, and superstition. Participants judged whether they considered them as true (belief) or not (disbelief) and reported their certainty in the decision. We found belief-associated activations in bilateral dorsolateral prefrontal cortex, left superior parietal cortex, and left lateral frontopolar cortex. Disbelief-associated activations were found in an anterior temporal cluster extending into the amygdala. We found a larger deactivation for disbelief than belief in the ventromedial prefrontal cortex that was most pronounced during decisions, suggesting a role of the vmPFC in belief-related decision-making. As a category-specific effect, we found disbelief-associated activation in retrosplenial cortex and parahippocampal gyrus for conspiracy theory statements. Exploratory analyses identified networks centered at anterior cingulate cortex for certainty, and dorsomedial prefrontal cortex for uncertainty. The uncertainty effect identifies a neural substrate for Alexander Bain's notion from 1859 of uncertainty as the real opposite of belief. Taken together, our results suggest a two-factor neural process model of belief with falsehood/veracity and uncertainty/certainty factors.

Generalization and discrimination of inhibitory avoidance differentially engage anterior and posterior retrosplenial subregions.

In a variety of behavioral procedures animals will show selective fear responding in shock-associated contexts, but not in other contexts. However, several factors can lead to generalized fear behavior, where responding is no longer constrained to the conditioning context and will transfer to novel contexts. Here, we assessed memory generalization using an inhibitory avoidance paradigm to determine if generalized avoidance behavior engages the retrosplenial cortex (RSC). Male and female Long Evans rats received inhibitory avoidance training prior to testing in the same context or a shifted context in two distinct rooms; one room that had fluorescent lighting (Light) and one that had red LED lighting (Dark). We found that animals tested in a light context maintained context-specificity; animals tested in the same context as training showed longer latencies to cross and animals tested in the shifted context showed shorter latencies to cross. However, animals tested in the dark generalized their avoidance behavior; animals tested in the same context and animals tested in the shifted context showed similarly-high latencies to cross. We next examined expression of the immediate early gene zif268 and perineuronal nets (PNNs) following testing and found that while activity in the basolateral amygdala corresponded with overall levels of avoidance behaviors, anterior RSC (aRSC) activity corresponded with learned avoidance generally, but posterior RSC (pRSC) activity seemed to correspond with generalized memory. PNN reduction in the RSC was associated with memory formation and retrieval, suggesting a role for PNNs in synaptic plasticity. Further, PNNs did not reduce in the RSC in animals who showed a generalized avoidance behavior, in line with their hypothesized role in memory consolidation. These findings suggest that there is differential engagement of retrosplenial subregions along the rostrocaudal axis to generalization and discrimination.

The precuneus as a central node in declarative memory retrieval.

Both, the hippocampal formation and the neocortex are contributing to declarative memory, but their functional specialization remains unclear. We investigated the differential contribution of both memory systems during free recall of word lists. In total, 21 women and 17 men studied the same list but with the help of different encoding associations. Participants associated the words either sequentially with the previous word on the list, with spatial locations on a well-known path, or with unique autobiographical events. After intensive rehearsal, subjects recalled the words during functional magnetic resonance imaging (fMRI). Common activity to all three types of encoding associations was identified in the posterior parietal cortex, in particular in the precuneus. Additionally, when associating spatial or autobiographical material, retrosplenial cortex activity was elicited during word list recall, while hippocampal activity emerged only for autobiographically associated words. These findings support a general, critical function of the precuneus in episodic memory storage and retrieval. The encoding-retrieval repetitions during learning seem to have accelerated hippocampus-independence and lead to direct neocortical integration in the sequentially associated and spatially associated word list tasks. During recall of words associated with autobiographical memories, the hippocampus might add spatiotemporal information supporting detailed scenic and contextual memories.

Strategy updating mediated by specific retrosplenial-parafascicular-basal ganglia networks

Adaptive behavior requires flexible control over learning and exploitation of potentially viable options. Within a particular task, careful learning of strategies that differ from the initially learned rule is especially important as it sets an individual's strategy repertoire. However, whether and how such strategy updating is mediated by specific brain networks has remained unclear. Retrosplenial cortex (RSC), a cortical area exhibiting extensive connectivity to dorso-medial striatum (DMS) and the hippocampal formation, has been broadly implicated in flexible learning and might be involved in strategy updating. Here, we investigate the specific role of mouse RSC in flexible learning, map relevant RSC-anchored cortico-thalamo-basal ganglia circuits, and dissect their role in strategy updating. Activity in RSC was neither required for initial rule learning nor to switch between previously learned rules but was specifically required to explore and learn new alternative options when previous ones were available but no longer appropriate. Such strategy updating depended on activity in RSC c-Fos+ ensembles associated with the original rule and on their connections to DMS and thalamic parafascicular nucleus (PF) neurons. At the circuit level, rule-related RSC projection neurons branched to innervate both DMS and PF neurons and mediated strategy updating through a RSC-DMS-substantia nigra reticulata (SNr)-PF network, coupling alternative exploration to outcome. In addition, a separate RSC-PF-RSC looped network promoted alternative exploration. Our results uncover cortico-basal ganglia-thalamo and cortico-thalamo networks involving subpopulations of neurons in RSC and PF that specifically control and implement strategy updating.

Sense of self impacts spatial navigation and hexadirectional coding in human entorhinal cortex

Grid cells in entorhinal cortex (EC) encode an individual’s location in space and rely on environmental cues and self-motion cues derived from the individual’s body. Body-derived signals are also primary signals for the sense of self and based on integrated sensorimotor signals (proprioceptive, tactile, visual, motor) that have been shown to enhance self-centered processing. However, it is currently unknown whether such sensorimotor signals that modulate self-centered processing impact grid cells and spatial navigation. Integrating the online manipulation of bodily signals, to modulate self-centered processing, with a spatial navigation task and an fMRI measure to detect grid cell-like representation (GCLR) in humans, we report improved performance in spatial navigation and decreased GCLR in EC. This decrease in entorhinal GCLR was associated with an increase in retrosplenial cortex activity, which was correlated with participants’ navigation performance. These data link self-centered processes during spatial navigation to entorhinal and retrosplenial activity and highlight the role of different bodily factors at play when navigating in VR.

Correlation between Alteration of Sharp-wave Ripple Coupled Cortical Oscillation and Long-term Memory Deficit in Alzheimer Disease Model Mice.

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by prominent episodic memory dysfunction. Recent studies have suggested that there is a sequential mechanism in the memory deficit, with long-term ones preceding short-term ones. However, there is lack of explanation for these symptoms. Interaction between the hippocampus and retrosplenial cortex (RSC) during slow-wave sleep (SWS) is a crucial step for successful long-term memory formation. In particular, sharp-wave ripple (SWR) is a principal hippocampus oscillation that coordinates with RSC activity. To determine the relationship between memory dysfunction and SWR-related oscillation changes in AD, we implanted local field potential electrodes in the hippocampus and RSC of AD model mice (APP/PS1). We found that the SWR-coupled ripple wave increased in the RSC, while the amplitude of the SWR was preserved. In addition, the corresponding delta power in hippocampus and RSC was elevated, together with altered delta synchrony in AD mice. All these findings showed a significant correlation with long-term memory deficits measured in contextual fear conditions. Our study suggests that altered SWR-coupled oscillations are a possible underlying mechanism of episodic memory dysfunction in AD mice.

A distributed circuit for associating environmental context with motor choice in retrosplenial cortex.

During navigation, animals often use recognition of familiar environmental contexts to guide motor action selection. The retrosplenial cortex (RSC) receives inputs from both visual cortex and subcortical regions required for spatial memory and projects to motor planning regions. However, it is not known whether RSC is important for associating familiar environmental contexts with specific motor actions. We test this possibility by developing a task in which motor trajectories are chosen based on the context. We find that mice exhibit differential predecision activity in RSC and that optogenetic suppression of RSC activity impairs task performance. Individual RSC neurons encode a range of task variables, often multiplexed with distinct temporal profiles. However, the responses are spatiotemporally organized, with task variables represented along a posterior-to-anterior gradient along RSC during the behavioral performance, consistent with histological characterization. These results reveal an anatomically organized retrosplenial cortical circuit for associating environmental contexts with appropriate motor outputs.

Increased Hippocampal Excitability and Altered Learning Dynamics Mediate Cognitive Mapping Deficits in Human Aging.

Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn spatial environments deteriorates substantially but the underlying neural mechanisms are not well understood. Here, we report findings from a behavioral and a fMRI experiment where healthy human older and younger adults of either sex performed a spatial learning task in a photorealistic virtual environment (VE). We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex (RSC)/parieto-occipital sulcus (POS) and anterior hippocampus did not change systematically as a function learning in older compared with younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits were linked to an increase in hippocampal excitability. Together, these results provide novel insights into how human aging affects computations in the brain's navigation system, highlighting the critical role of the hippocampus.SIGNIFICANCE STATEMENT Key structures of the brain's navigation circuit are particularly vulnerable to the deleterious consequences of aging, and declines in spatial navigation are among the earliest indicators for a progression from healthy aging to neurodegenerative diseases. Our study is among the first to provide a mechanistic account about how physiological changes in the aging brain affect the formation of spatial knowledge. We show that neural activity in the aging hippocampus and medial parietal areas is decoupled from individual learning states across repeated episodes in a novel spatial environment. Importantly, we find that increased excitability of the anterior hippocampus might constitute a potential neural mechanism for cognitive mapping deficits in old age.

Neuronal Encoding of Object‐Type and Object‐Place Memories in Hippocampus and Neocortex of Young and Old Mice

Neuronal encoding of environmental information has long been in the focus of neuroscience. Neurophysiological studies show that when animals become familiar with space or objects, neuronal activity changes due to these factors. However, despite a considerable amount of experimental data, the specific neural bases of space and objects encoding, and the nature of their disturbance in aging or pathology remains an open question. In this work, we test the hypothesis that neurons in different regions of the brain, hippocampus and retrosplenial cortex (RSC) encode spatial and object information respectively, and that natural aging impairs these two forms of memory differently. To test this hypothesis, we developed an approach combining optical recording of neuronal activity and assessment of animal behavior during novel object recognition (NOR) and object place recognition (OPR) tasks, as well as cognitive enhancement in young and old animals. First, we examined what forms of memory are affected in old mice, and whether it is possible to restore the age‐impaired memory pharmacologically. We trained young (2–3 months) and old (18–21 months) mice in NOR and OPR tasks and then tested short‐term 120 min memory and long‐term 24 h memory. We showed that both young and old mice demonstrate short‐term NOR and OPR memories, and that P2 cognitive enhancer that belongs to a new class of sAPP‐mimetics did not potentiate this memory. On the other hand, both old and young mice failed to form NOR and OPR long‐term memories. Interestingly, administration of P2 produced long‐term memory manifestation only in the old mice.Next, we recorded the object‐type and object‐place related calcium activity in the RSC and hippocampus CA1 of young mice using genetically encoded YtnC sensor and fiber‐optic photometry (Fig. 1, A). We found an increase in the number of calcium events in the RSC when animals examined new position of the familiar object. We also discovered decrease in the RSC activity during exploration of a novel object.Using multiphoton microscopy and NVista minimicroscopy we registered GCaMP6 calcium activity of identified RSC (Fig. 1, B) and CA1 (Fig. 1, C) neurons in young mice during NOR and OPR tasks performed in the Mobile HomeCage. Different classes of neurons were identified – those demonstrating an increase and decrease of activity during place and objects exploration, as well as cells that were active during specific behavioral acts.Thus, we showed that both object‐type and object‐place memory was specifically expressed in the activity of RSC and CA1 neurons. Both object‐type and object‐place long‐term memories were missing in the old mice but were brought to the surface by administration sAPP‐mimetic cognitive enhancer. In the future, we will test how memory‐related brain activity changes in NOR and OPR tasks in old animals, and whether these changes in neuronal activity could be compensated pharmacologically.Support or Funding InformationSupported by RSF 20‐15‐00283 and RFBR 17‐00‐00215, 19‐315‐80020, 17‐29‐07083, 18‐32‐20212Neuronal calcium activity in novel object recognition and object place recognition tasks. A: fiber‐optic photometry of YtnC calcium signal from retrosplenial cortex (RSC) and hippocampus CA1; red line – baseline. B: two‐photon microscopy of identified GCaMP6S neurons in the retrosplenial cortex; asterisks show calcium events – spikes. Ñ: NVista minimicroscopy of GCaMP6S neurons in hippocampus CA1; arrows show calcium spikes.Figure 1

A model of path integration and representation of spatial context in the retrosplenial cortex.

Inspired by recent biological experiments, we simulate animals moving in different environments (open space, spiral mazes and on a treadmill) to test the performances of a simple model of the retrosplenial cortex (RSC) acting as a path integration (PI) and as a categorization mechanism. The connection between the hippocampus, RSC and the entorhinal cortex is revealed through a novel perspective. We suppose that the path integration is performed by the information coming from RSC. Grid cells in the entorhinal cortex then can be built as the result of a modulo projection of RSC activity. In our model, PI is performed by a 1D field of neurons acting as a simple low-pass filter of head direction (HD) cells modulated by the linear velocity of the animal. Our paper focuses on the constraints on the HD cells shape for a good approximation of PI. Recording of neurons on our 1D PI field shows these neurons would not be intuitively interpreted as performing PI. Using inputs coming from a narrow neighbouring projection of our PI field creates place cell-like activities in the RSC when the mouse runs on the treadmill. This can be the result of local self-organizing maps representing blobs of neurons in the RSC (e.g. cortical columns). Other simulations show that accessing the whole PI field would induce place cells whatever the environment is. Since this property is not observed, we conclude that the categorization neurons in the RSC should have access to only a small fraction of the PI field.

Vision and Locomotion Combine to Drive Path Integration Sequences in Mouse Retrosplenial Cortex.

The retrosplenial cortex (RSC) is involved in a broad range of cognitive functions, integrating rich sensory, motor, and spatial signals from multiple brain areas, including the hippocampal system. RSC neurons show hippocampus-dependent activity reminiscent of place cell sequences. Using cellular calcium imaging in a virtual reality (VR)-based locomotion task, we investigate how the integration of visual and locomotor inputs may give rise to such activity in RSC. A substantial population shows neural sequences that track position in the VR environment. This activity is driven by the conjunction of visual stimuli sequences and active movement, which is suggestive of path integration. The activity is anchored to a reference point and predominantly follows the VR upon manipulations of optic flow against locomotion. Thus, locomotion-gated optic flow, combined with the presence of contextual cues at the start of each trial, is sufficient to drive the sequential activity. A subpopulation shows landmark-related visual responses that are modulated by animal's position in the VR. Thus, rather than fragmenting the spatial representationinto equivalent locomotion-based ensemble versus optic-flow-based ensemble, in RSC, optic flow appears to override locomotion signals coherently in the population, when the gain betweenthe two signals is altered.

Hippocampal Ripple Coordinates Retrosplenial Inhibitory Neurons during Slow-Wave Sleep

SUMMARYThe hippocampus and retrosplenial cortex (RSC) play indispensable roles in memory formation, and importantly, a hippocampal oscillation known as ripple is key to consolidation of new memories. However, it remains unclear how the hippocampus and RSC communicate and the role of ripple oscillation in coordinating the activity between these two brain regions. Here, we record from the dorsal hippocampus and RSC simultaneously in freely behaving mice during sleep and reveal that the RSC displays a pre-ripple activation associated with slow and fast oscillations. Immediately after ripples, a subpopulation of RSC putative inhibitory neurons increases firing activity, while most RSC putative excitatory neurons decrease activity. Consistently, optogenetic stimulation of this hippocampus-RSC pathway activates and suppresses RSC putative inhibitory and excitatory neurons, respectively. These results suggest that the dorsal hippocampus mainly inhibits RSC activity via its direct innervation of RSC inhibitory neurons, which overshadows the RSC in supporting learning and memory functions.

Hippocampal Ripple Communicates with Retrosplenial Inhibitory Neurons During Slow-Wave Sleep

The hippocampus and retrosplenial cortex (RSC) both play indispensable roles in memory formation, and, importantly, a hippocampal oscillation known as ripple is key to the consolidation of new memory. However, it remains unclear how the hippocampus and RSC communicate and the role of ripple oscillation in coordinating information exchange between these two brain regions. Here we recorded from the dorsal hippocampus and RSC simultaneously in freely-behaving mice during sleep and revealed that the RSC displayed a shift of fast-to-slow oscillations preceding hippocampal ripples. Immediately after ripples, a group of RSC putative inhibitory neurons increased firing activity, while most RSC putative excitatory neurons decreased activity. Consistently, optogenetic activation of this hippocampus-to-RSC pathway activates and suppresses RSC putative inhibitory and excitatory neurons, respectively. These results suggest that the dorsal hippocampus mainly inhibits RSC activity via its direct innervation of RSC inhibitory neurons, which overshadows the RSC in supporting learning and memory functions.

Dissociating Landmark Stability from Orienting Value Using Functional Magnetic Resonance Imaging.

Retrosplenial cortex (RSC) plays a role in using environmental landmarks to help orientate oneself in space. It has also been consistently implicated in processing landmarks that remain fixed in a permanent location. However, it is not clear whether the RSC represents the permanent landmarks themselves or instead the orienting relevance of these landmarks. In previous functional magnetic resonance imaging (fMRI) studies, these features have been conflated—stable landmarks were always useful for orienting. Here, we dissociated these two key landmark attributes to investigate which one best reflects the function of the RSC. Before scanning, participants learned the features of novel landmarks about which they had no prior knowledge. During fMRI scanning, we found that the RSC was more engaged when people viewed permanent compared with transient landmarks and was not responsive to the orienting relevance of landmarks. Activity in RSC was also related to the amount of landmark permanence information a person had acquired and, as knowledge increased, the more the RSC drove responses in the anterior thalamus while viewing permanent landmarks. In contrast, the angular gyrus and the hippocampus were engaged by the orienting relevance of landmarks, but not their permanence, with the hippocampus also sensitive to the distance between relevant landmarks and target locations. We conclude that the coding of permanent landmarks in RSC may drive processing in regions like anterior thalamus, with possible implications for the efficacy of functions such as navigation.

Heightened Responses of the Parahippocampal and Retrosplenial Cortices during Contextualized Recognition of Congruent Objects.

Context sometimes helps make objects more recognizable. Previous studies using functional magnetic resonance imaging (fMRI) have examined regional neural activity when objects have strong or weak associations with their contexts. Such studies have demonstrated that activity in the parahippocampal cortex (PHC) generally corresponds with strong associations between objects and their spatial contexts while retrosplenial cortex (RSC) activity is linked with episodic memory. However these studies investigated objects viewed in associated contexts, but the direct influence of scene on the perception of visual objects has not been widely investigated. We hypothesized that the PHC and RSC may only be engaged for congruent contexts in which the object could typically be found but not for neutral contexts. While in an fMRI scanner, 15 participants rated the recognizability of 152 photographic images of objects, presented within congruent and incongruent contexts. Regions of interest were created to examine PHC and RSC activity using a hypothesis-driven approach. Exploratory analyses were also performed to identify other regional activity. In line with previous studies, PHC and RSC activity emerged when objects were viewed in congruent contexts. Activity in the RSC, inferior parietal lobe (IPL) and fusiform gyrus also emerged. These findings indicate that different brain regions are employed when objects are meaningfully contextualized.

Efficacy of navigation may be influenced by retrosplenial cortex-mediated learning of landmark stability.

Human beings differ considerably in their ability to orient and navigate within the environment, but it has been difficult to determine specific causes of these individual differences. Permanent, stable landmarks are thought to be crucial for building a mental representation of an environment. Poor, compared to good, navigators have been shown to have difficulty identifying permanent landmarks, with a concomitant reduction in functional MRI (fMRI) activity in the retrosplenial cortex. However, a clear association between navigation ability and the learning of permanent landmarks has not been established. Here we tested for such a link. We had participants learn a virtual reality environment by repeatedly moving through it during fMRI scanning. The environment contained landmarks of which participants had no prior experience, some of which remained fixed in their locations while others changed position each time they were seen. After the fMRI learning phase, we divided participants into good and poor navigators based on their ability to find their way in the environment. The groups were closely matched on a range of cognitive and structural brain measures. Examination of the learning phase during scanning revealed that, while good and poor navigators learned to recognise the environment's landmarks at a similar rate, poor navigators were impaired at registering whether landmarks were stable or transient, and this was associated with reduced engagement of the retrosplenial cortex. Moreover, a mediation analysis showed that there was a significant effect of landmark permanence learning on navigation performance mediated through retrosplenial cortex activity. We conclude that a diminished ability to process landmark permanence may be a contributory factor to sub-optimal navigation, and could be related to the level of retrosplenial cortex engagement.

Chemogenetic silencing of neurons in retrosplenial cortex disrupts sensory preconditioning.

An essential aspect of episodic memory is the formation of associations between neutral sensory cues in the environment. In light of recent evidence that this critical aspect of learning does not require the hippocampus, we tested the involvement of the retrosplenial cortex (RSC) in this process using a chemogenetic approach that allowed us to temporarily silence neurons along the entire rostrocaudal extent of the RSC. A viral vector containing the gene for a synthetic inhibitory G-protein-coupled receptor (hM4Di) was infused into RSC. When the receptor was later activated by systemic injection of clozapine-N-oxide, neural activity in RSC was transiently silenced (confirmed using a patch-clamp procedure). Rats expressing hM4Di and control rats were trained in a sensory preconditioning procedure in which a tone and light were paired on some trials and a white noise stimulus was presented alone on the other trials during the Preconditioning phase. Thus, rats were given the opportunity to form an association between a tone and a light in the absence of reinforcement. Later, the light was paired with food. During the test phase when the auditory cues were presented alone, controls exhibited more conditioned responding during presentation of the tone compared with the white noise reflecting the prior formation of a tone-light association. Silencing RSC neurons during the Preconditioning phase prevented the formation of an association between the tone and light and eliminated the sensory preconditioning effect. These findings indicate that RSC may contribute to episodic memory formation by linking essential sensory stimuli during learning.

The Neural Basis of Contextual Influences on Face Categorization

From only brief exposure to a face, individuals spontaneously categorize another's race. Recent behavioral evidence suggests that visual context may affect such categorizations. We used fMRI to examine the neural basis of contextual influences on the race categorization of faces. Participants categorized the race of faces that varied along a White-Asian morph continuum and were surrounded by American, neutral, or Chinese scene contexts. As expected, the context systematically influenced categorization responses and their efficiency (response times). Neuroimaging results indicated that the retrosplenial cortex (RSC) and orbitofrontal cortex (OFC) exhibited highly sensitive, graded responses to the compatibility of facial and contextual cues. These regions showed linearly increasing responses as a face became more White when in an American context, and linearly increasing responses as a face became more Asian when in a Chinese context. Further, RSC activity partially mediated the effect of this face-context compatibility on the efficiency of categorization responses. Together, the findings suggest a critical role of the RSC and OFC in driving contextual influences on face categorization, and highlight the impact of extraneous cues beyond the face in categorizing other people.

Refreshing and Integrating Visual Scenes in Scene-selective Cortex

Constructing a rich and coherent visual experience involves maintaining visual information that is not perceptually available in the current view. Recent studies suggest that briefly thinking about a stimulus (refreshing) can modulate activity in category-specific visual areas. Here, we tested the nature of such perceptually refreshed representations in the parahippocampal place area (PPA) and retrosplenial cortex (RSC) using fMRI. We asked whether a refreshed representation is specific to a restricted view of a scene, or more view-invariant. Participants saw a panoramic scene and were asked to think back to (refresh) a part of the scene after it disappeared. In some trials, the refresh cue appeared twice on the same side (e.g., refresh left-refresh left), and other trials, the refresh cue appeared on different sides (e.g., refresh left-refresh right). A control condition presented halves of the scene twice on same sides (e.g., perceive left-perceive left) or different sides (e.g., perceive left-perceive right). When scenes were physically repeated, both the PPA and RSC showed greater activation for the different-side repetition than the same-side repetition, suggesting view-specific representations. When participants refreshed scenes, the PPA showed view-specific activity just as in the physical repeat conditions, whereas RSC showed an equal amount of activation for different- and same-side conditions. This finding suggests that in RSC, refreshed representations were not restricted to a specific view of a scene, but extended beyond the target half into the entire scene. Thus, RSC activity associated with refreshing may provide a mechanism for integrating multiple views in the mind.

Early-onset dysfunction of retrosplenial cortex precedes overt amyloid plaque formation in Tg2576 mice

A mouse model of amyloid pathology was used to first examine using a cross sectional design changes in retrosplenial cortex activity in transgenic mice aged 5, 11, 17, and 23 months. Attention focused on: (1) overt amyloid labeled with β-amyloid (1–42) and Congo Red staining, (2) metabolic function assessed by the enzyme, cytochrome oxidase, and (3) neuronal activity as assessed indirectly by the immediate-early gene (IEG), c-Fos. Changes in cytochrome oxidase and c-Fos activity were observed in the retrosplenial cortex in Tg2576 mice as early as 5 months of age, long before evidence of plaque formation. Subsequent analyses concentrating on this early dysfunction revealed at 5 months pervasive, amyloid precursor protein (APP)-derived peptide accumulation in the retrosplenial cortex and selective afferents (anterior thalamus, hippocampus), which was associated with the observed c-Fos hyporeactivity. These findings indicate that retrosplenial cortex dysfunction occurs during early stages of amyloid production in Tg2576 mice and may contribute to cognitive dysfunction.