Retrosplenial Cortex Research Articles

Toxoplasma gondii Infection of Alzheimer's Disease Mice Reduces Brain Amyloid Density Globally and Regionally.

Toxoplasma gondii infection of Alzheimer's disease model mice decreases amyloid β plaques. We aimed to determine if there is a brain regional difference in amyloid β reduction in the brains of T. gondii-infected compared to control mice. Three-month-old 5xFAD (AD model) mice were injected with T. gondii or with phosphate-buffered saline as a control. Intact brains were harvested at 6 weeks postinfection, optically cleared using iDISCO+, and brain-wide amyloid burden was visualized using volumetric light-sheet imaging. Amyloid signal was quantified across each brain and computationally mapped to the Allen Institute Brain Reference Atlas to determine amyloid density in each region. A brain-wide analysis of amyloid in control and T. gondii-infected 5xFAD mice revealed that T. gondii infection decreased amyloid burden in the brain globally as well as in the cortex and hippocampus, and many daughter regions. Daughter regions that showed reduced amyloid burden included the prelimbic cortex, visual cortex, and retrosplenial cortex. The olfactory tubercle, a region known to have increased monocytes following T. gondii infection, also showed reduced amyloid after infection. T. gondii infection of AD mice reduces amyloid burden in a brain region-specific manner that overlaps with known regions of T. gondii infection and peripheral immune cell infiltration.

Astrocytic P2X7 receptor in retrosplenial cortex drives electroacupuncture analgesia.

P2X7 receptor (P2X7R) has been found to contribute to the peripheral mechanism of acupuncture analgesia (AA). However, whether it plays an important role in central mechanism remains unknown. In this study, we aimed to reveal the role of astrocytic P2X7R in retrosplenial cortex (RSC) in AA and provide new evidence for underlying the central mechanism of AA. We applied the chemogenetic receptors hM3Dq to stimulate or hM4Di to inhibit astrocytes ligand clozapine-N-oxide (CNO) following injection of adeno-associated virus (AAV) into the bilateral RSC, or pharmacologically intervened in the activity of the purinergic receptor P2X7R. Current data indicated that chemogenetic inhibition of astrocytes or injection of P2X7R agonist Bz-ATP in the bilateral RSC significantly reverses the analgesic effect of electroacupuncture (EA) in formalin tests while the bilateral injection of the P2X7R antagonist A438079 alleviated formalin-induced nociceptive behavior. Additionally, chemogenetic suppression of astrocytic P2X7R by injection of AAV in the bilateral RSC decreased hind paw flinches induced by formalin in the mice. These findings indicate the participation of both astrocytes and P2X7R in the RSC in EA analgesic. Moreover, P2X7R on astrocytes in the RSC appears to play a critical role in the ability of EA to attenuate formalin-induced pain responses in mice.

Prosopagnosie et syndrome de Capgras : deux syndromes en miroir ?

First described in the 19th century in patients with brain lesions, prosopagnosia was named in 1947 by Joachim Bodamer (1910–1985), a German neuropsychiatrist. The term refers to the inability to recognise a familiar face, a rarely isolated symptom. Prosopagnosia is thought to result from brain lesions, predominantly at the ventral right temporo-occipital junction. There are more common cases of developmental prosopagnosia, where no lesion has been identified. Capgras syndrome (CS), described by Joseph Capgras (1873–1950), a psychiatrist, consists of the persistent belief that a close relative, identified, has been replaced by a look-alike. SC, considered a delusional disorder of identification or familiarity, has been described in chronic psychoses, mainly schizophrenia. It is also reported in the course of neurodegenerative diseases (mainly Alzheimer's disease, Lewy body dementia, Parkinson's dementia). Lesion-based forms have recently been described. Prosopagnosia and SC were initially thought to result from mirror-image lesions involving a single factor, one affecting an overt ventral circuit for face recognition (in the case of prosopagnosia), the other a covert dorsal circuit involved in emotional and vegetative responses (in the case of CS). Lesion network mapping has been used in both lesion-related conditions and suggests a more complex figure. Lesions causing prosopagnosia were correlated with one of the main regions associated with face recognition, the right fusiform face area, and anticorrelated with left frontal regions possibly involved in visual attentional control. In lesional forms of CS or other delusional misidentification syndromes, there was a correlation with left retrosplenial cortex, an area associated with familiarity processing, and a correlation with right frontal regions associated with belief evaluation. This finding supports the intervention of two factors in CS, one generating the impaired familiarity associated with perception and the other the genesis and persistence of a delusional idea. The debate on the mechanisms of CS is not settled, especially as it is limited to its lesional forms, but studies using lesion network mapping already mark a more general paradigm shift, with attention shifting from lesions (clinico-anatomical method) to circuit dysfunction.

Conjunctive processing of spatial border and locomotion in retrosplenial cortex during spatial navigation.

Spatial information and dynamic locomotor behaviours are equally important for achieving locomotor goals during spatial navigation. However, it remains unclear how spatial and locomotor information is integrated during the processing of self-initiated spatial navigation. Anatomically, the retrosplenial cortex (RSC) has reciprocal connections with brain regions related to spatial processing, including the hippocampus and para-hippocampus, and also receives inputs from the secondary motor cortex. In addition, RSC is functionally associated with allocentric and egocentric spatial targets and head-turning. So, RSC may be a critical region for integrating spatial and locomotor information. In this study, we first examined the role of RSC in spatial navigation using the Morris water maze and found that mice with inactivated RSC took a longer time and distance to reach their destination. Then, by imaging neuronal activity in freely behaving mice within two open fields of different sizes, we identified a large proportion of border cells, head-turning cells and locomotor speed cells in the superficial layer of RSC. Interestingly, some RSC neurons exhibited conjunctive coding for both spatial and locomotor signals. Furthermore, these conjunctive neurons showed higher prediction accuracy compared with simple spatial or locomotor neurons in special navigator scenes using the border, turning and positive-speed conjunctive cells. Our study reveals that the RSC is an important conjunctive brain region that processes spatial and locomotor information during spatial navigation. KEY POINTS: Retrosplenial cortex (RSC) is indispensable during spatial navigation, which was displayed by the longer time and distance of mice to reach their destination after the inactivation of RSC in a water maze. The superficial layer of RSC has a larger population of spatial-related border cells, and locomotion-related head orientation and speed cells; however, it has few place cells in two-dimensional spatial arenas. Some RSC neurons exhibited conjunctive coding for both spatial and locomotor signals, and the conjunctive neurons showed higher prediction accuracy compared with simple spatial or locomotor neurons in special navigation scenes. Our study reveals that the RSC is an important conjunctive brain region that processes both spatial and locomotor information during spatial navigation.

Time cells in the retrosplenial cortex.

The retrosplenial cortex (RSC) is a key component of the brain's memory systems, with anatomical connections to the hippocampus, anterior thalamus, and entorhinal cortex. This circuit has been implicated in episodic memory and many of these structures have been shown to encode temporal information, which is critical for episodic memory. For example, hippocampal time cells reliably fire during specific segments of time during a delay period. Although RSC lesions are known to disrupt temporal memory, time cells have not been observed there. In this study, we reanalyzed archival RSC neuronal firing data during the intertrial delay period from two previous experiments involving different behavioral tasks, a blocked alternation task and a cued T-maze task. For the blocked alternation task, rats were required to approach the east or west arm of a plus maze for reward during different blocks of trials. Because the reward locations were not cued, the rat had to remember the goal location for each trial. In the cued T-maze task, the reward location was explicitly cued with a light and the rats simply had to approach the light for reward, so there was no requirement to hold a memory during the intertrial delay. Time cells were prevalent in the blocked alternation task, and most time cells clearly differentiated the east and west trials. We also found that RSC neurons could exhibit off-response time fields, periods of reliably inhibited firing. Time cells were also observed in the cued T-maze, but they were less prevalent and they did not differentiate left and right trials as well as in the blocked alternation task, suggesting that RSC time cells are sensitive to the memory demands of the task. These results suggest that temporal coding is a prominent feature of RSC firing patterns, consistent with an RSC role in episodic memory.

Effect of Repetitive Transcranial Magnetic Stimulation on Post-Stroke Comorbid Cognitive Impairment and Depression: A Randomized Controlled Trial.

There are currently no uniform treatments for post-stroke comorbid cognitive impairment and depression (PSCCID). To verify whether repetitive transcranial magnetic stimulation (rTMS) can improve PSCCID symptoms and explore the underlying roles of resting-state functional magnetic resonance imaging (rs-fMRI). Thirty PSCCID patients were randomized in a 1 : 1 ratio to receive 4 weeks of rTMS (intervention group) or sham rTMS (control group) over the left dorsolateral prefrontal cortex (DLPFC). rs-fMRI was acquired to analyze the functional plasticity of brain regions at baseline and immediately after the last intervention. Cognition, depression status, and neural electrophysiology were improved in both intervention and control groups after treatment (p = 0.015-0.042), and the intervention group had more significant improvement than the control group. Analysis of functional connectivities (FCs) within the default mood network (DMN) showed that the connection strength of the left temporal pole/left parahippocampal cortex and right lateral temporal cortex/right retrosplenial cortex in the intervention group were enhanced compared with its pre-intervention and that in the control group after treatment (p < 0.05), and the both FC values were positively correlated with MMSE scores (p < 0.001). The intervention group had stronger FCs within the DMN compared with the control group after treatment, and some of the enhanced FCs were correlated with the P300 latency and amplitude. rTMS over the left DLPFC is an effective treatment for improving both cognitive impairment and depression among patients with PSCCID. The enhanced FCs within the DMN may serve as a compensatory functional recombination to promote clinical recovery.

Egocentric neural representation of geometric vertex in the retrosplenial cortex

Egocentric neural representations of environmental features, such as edges and vertices, are important for constructing a geometrically detailed egocentric cognitive map for goal-directed navigation and episodic memory. While egocentric neural representations of edges like egocentric boundary/border cells exist, those that selectively represent vertices egocentrically are yet unknown. Here we report that granular retrosplenial cortex (RSC) neurons in male mice generate spatial receptive fields exclusively near the vertices of environmental geometries during free exploration, termed vertex cells. Their spatial receptive fields occurred at a specific orientation and distance relative to the heading direction of mice, indicating egocentric vector coding of vertex. Removing physical boundaries defining the environmental geometry abolished the egocentric vector coding of vertex, and goal-directed navigation strengthened the egocentric vector coding at the goal-located vertex. Our findings suggest that egocentric vector coding of vertex by granular RSC neurons helps construct an egocentric cognitive map that guides goal-directed navigation.

Subclinical brain manifestations of repeated mild traumatic brain injury are changed by chronic exposure to sleep loss, caffeine, and sleep aids

IntroductionAfter mild traumatic brain injury (mTBI), the brain is labile for weeks and months and vulnerable to repeated concussions. During this time, patients are exposed to everyday circumstances that, in themselves, affect brain metabolism and blood flow and neural processing. How commonplace activities interact with the injured brain is unknown. The present study in an animal model investigated the extent to which three commonly experienced exposures—daily caffeine usage, chronic sleep loss, and chronic sleep aid medication—affect the injured brain in the chronic phase. MethodsSubclinical trauma by repeated mTBIs was produced by our head rotational acceleration injury model, which causes brain injury consistent with the mechanism of concussion in humans. Forty-eight hours after a third mTBI, chronic administrations of caffeine, sleep restriction, or zolpidem (sedative hypnotic) began and were continued for 70 days. On Days 30 and 60 post injury, resting state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) were performed. ResultsChronic caffeine, sleep restriction, and zolpidem each changed the subclinical brain characteristics of mTBI at both 30 and 60 days post injury, detected by different MRI modalities. Each treatment caused microstructural alterations in DTI metrics in the insular cortex and retrosplenial cortex compared with mTBI, but also uniquely affected other gray and white matter regions. Zolpidem administration affected the largest number of individual structures in mTBI at both 30 and 60 days, and not necessarily toward normalization (sham treatment). Chronic sleep restriction changed local functional connectivity at 30 days in diametrical opposition to chronic caffeine ingestion, and both treatment outcomes were different from sham, mTBI-only and zolpidem comparisons. The results indicate that commonly encountered exposures modify subclinical brain activity and structure long after healing is expected to be complete. ConclusionsChanges in activity and structure detected by fMRI are widely understood to reflect changes in the functions of the affected region which conceivably underlie mTBI neuropathology and symptomatology in the chronic phase after injury.

Learning to use landmarks for navigation amplifies their representation in retrosplenial cortex.

Visual landmarks provide powerful reference signals for efficient navigation by altering the activity of spatially tuned neurons, such as place cells, head direction cells, and grid cells. To understand the neural mechanism by which landmarks exert such strong influence, it is necessary to identify how these visual features gain spatial meaning. In this study, we characterized visual landmark representations in mouse retrosplenial cortex (RSC) using chronic two-photon imaging of the same neuronal ensembles over the course of spatial learning. We found a pronounced increase in landmark-referenced activity in RSC neurons that, once established, remained stable across days. Changing behavioral context by uncoupling treadmill motion from visual feedback systematically altered neuronal responses associated with the coherence between visual scene flow speed and self-motion. To explore potential underlying mechanisms, we modeled how burst firing, mediated by supralinear somatodendritic interactions, could efficiently mediate context- and coherence-dependent integration of landmark information. Our results show that visual encoding shifts to landmark-referenced and context-dependent codes as these cues take on spatial meaning during learning.

Subsequent Memory Effects in Cortical Pattern Similarity Differ by Semantic Class.

Although living and nonliving stimuli are known to rely on distinct brain regions during perception, it is largely unknown if their episodic memory encoding mechanisms differ as well. To investigate this issue, we asked participants to encode object pictures (e.g., a picture of a tiger) and to retrieve them later in response to their names (e.g., word "tiger"). For each of four semantic classes (living-animate, living-inanimate, nonliving-large, and nonliving-small), we examined differences in the similarity in activation patterns (neural pattern similarity [NPS]) for subsequently remembered versus forgotten items. Higher NPS for remembered items suggests an advantage of within-class item similarity, whereas lower NPS for remembered items indicates an advantage for item distinctiveness. We expect NPS within class-specific regions to be higher for remembered than for forgotten items. For example, the parahippocampal cortex has a well-known role in scene processing [Aminoff, E. M., Kveraga, K., & Bar, M. The role of the parahippocampal cortex in cognition. Trends in Cognitive Sciences, 17, 379-390, 2013], and the anterior temporal and inferior frontal gyrus have well-known roles in object processing [Clarke, A., & Tyler, L. K. Object-specific semantic coding in human perirhinal cortex. Journal of Neuroscience, 34, 4766-4775, 2014]. As such, we expect to see higher NPS for remembered items in these regions pertaining to scenes and objects, respectively. Consistent with this hypothesis, in fusiform, parahippocampal, and retrosplenial regions, higher NPS predicted memory for subclasses of nonliving objects, whereas in the left inferior frontal and left retrosplenial regions, lower NPS predicted memory for subclasses of living objects. Taken together, the results support the idea that subsequent memory depends on a balance of similarity and distinctiveness and demonstrate that the neural mechanisms of episodic encoding differ across semantic categories.

Neural signatures of default mode network subsystems in first-episode, drug-naive patients with major depressive disorder after 6-week thought induction psychotherapy treatment.

Evidence indicates that the default mode network (DMN) plays a crucial role in the neuropathology of major depressive disorder (MDD). However, the neural signatures of DMN subsystems in MDD after low resistance Thought Induction Psychotherapy (TIP) remain incompletely understood. We collected functional magnetic resonance imaging data from 20 first-episode, drug-naive MDD and 20 healthy controls (HCs). The DMN was segmented into three subsystems and seed-based functional connectivity (FC) was computed. After 6-week treatment, the significantly reduced FCs with the medial temporal lobe memory subsystem in MDD at baseline were enhanced and were comparable to that in HCs. Changed Hamilton Depression Rating Scale scores were significantly related with changed FC between the posterior cingulate cortex (PCC) and the right precuneus (PCUN). Further, changed serotonin 5-hydroxytryptamine levels were significantly correlated with changed FCs between the PCC and the left PCUN, between the posterior inferior parietal lobule and the left inferior temporal gyrus, and between the retrosplenial cortex and the right inferior frontal gyrus, opercular part. Finally, the support vector machine obtained an accuracy of 67.5% to distinguish between MDD at baseline and HCs. These findings may deepen our understanding of the neural basis of the effects of TIP on DMN subsystems in MDD.

Differential stability of task variable representations in retrosplenial cortex

Cortical neurons store information across different timescales, from seconds to years. Although information stability is variable across regions, it can vary within a region as well. Association areas are known to multiplex behaviorally relevant variables, but the stability of their representations is not well understood. Here, we longitudinally recorded the activity of neuronal populations in the mouse retrosplenial cortex (RSC) during the performance of a context-choice association task. We found that the activity of neurons exhibits different levels of stability across days. Using linear classifiers, we quantified the stability of three task-relevant variables. We find that RSC representations of context and trial outcome display higher stability than motor choice, both at the single cell and population levels. Together, our findings show an important characteristic of association areas, where diverse streams of information are stored with varying levels of stability, which may balance representational reliability and flexibility according to behavioral demands.

Coordination between midcingulate cortex and retrosplenial cortex in pain regulation.

The cingulate cortex, with its subregions ACC, MCC, and RSC, is key in pain processing. However, the detailed interactions among these regions in modulating pain sensation have remained unclear. In this study, chemogenetic tools were employed to selectively activate or inhibit neuronal activity in the MCC and RSC of rodents to elucidate their roles in pain regulation.Results: Our results showed that chemogenetic activation in both the RSC and MCC heightened pain sensitivity. Suppression of MCC activity disrupted the RSC's regulation of both mechanical and thermal pain, while RSC inhibition specifically affected the MCC's regulation of thermal pain. The findings indicate a complex interplay between the MCC and RSC, with the MCC potentially governing the RSC's pain regulatory mechanisms. The RSC, in turn, is crucial for the MCC's control over thermal sensation, revealing a collaborative mechanism in pain processing. This study provides evidence for the MCC and RSC's collaborative roles in pain regulation, highlighting the importance of their interactions for thermal and mechanical pain sensitivity. Understanding these mechanisms could aid in developing targeted therapies for pain disorders.

Pan-cortical cellular imaging in freely behaving mice using a miniaturized micro-camera array microscope (mini-MCAM).

Understanding how circuits in the brain simultaneously coordinate their activity to mediate complex ethnologically relevant behaviors requires recording neural activities from distributed populations of neurons in freely behaving animals. Current miniaturized imaging microscopes are typically limited to imaging a relatively small field of view, precluding the measurement of neural activities across multiple brain regions. Here we present a miniaturized micro-camera array microscope (mini-MCAM) that consists of four fluorescence imaging micro-cameras, each capable of capturing neural activity across a 4.5 mm x 2.55 mm field of view (FOV). Cumulatively, the mini-MCAM images over 30 mm2 area of sparsely expressed GCaMP6s neurons distributed throughout the dorsal cortex, in regions including the primary and secondary motor, somatosensory, visual, retrosplenial, and association cortices across both hemispheres. We demonstrate cortex-wide cellular resolution in vivo Calcium (Ca 2+ ) imaging using the mini-MCAM in both head-fixed and freely behaving mice.

Retrosplenial inputs drive visual representations in the medial entorhinal cortex

The importance of visual cues for navigation and goal-directed behavior is well established, although the neural mechanisms supporting sensory representations in navigational circuits are largely unknown. Navigation is fundamentally dependent on the medial entorhinal cortex (MEC), which receives direct projections from neocortical visual areas, including the retrosplenial cortex (RSC). Here, we perform high-density recordings of MEC neurons in awake, head-fixed mice presented with simple visual stimuli and assess the dynamics of sensory-evoked activity. We find that a large fraction of neurons exhibit robust responses to visual input. Visually responsive cells are located primarily in layer 3 of the dorsal MEC and can be separated into subgroups based on functional and molecular properties. Furthermore, optogenetic suppression of RSC afferents within the MEC strongly reduces visual responses. Overall, our results demonstrate that the MEC can encode simple visual cues in the environment that may contribute to neural representations of location necessary for accurate navigation.

Genoarchitectural Definition of the Adult Mouse Mesocortical Ring: A Contribution to Cortical Ring Theory.

Data mining was performed at the databases of the Allen Institute for Brain Science (RRID:SCR_017001) searching for genes expressed selectively throughout the adult mouse mesocortex (transitional cortex ring predicted within the concentric ring theory of mammalian cortical structure, in contrast with central isocortex [ICx] and peripheral allocortex). We aimed to explore a shared molecular profile selective of all or most mesocortex areas. This approach checks and corroborates the precision of other previous definitory criteria, such as poor myelination and high kainate receptor level. Another aim was to examine which cortical areas properly belong to mesocortex. A total of 34 positive adult selective marker genes of mesocortex were identified, jointly with 12 negative selective markers, making a total of 46 markers. All of them identify the same set of cortical areas surrounding the molecularly different ICx as well as excluding adjacent allocortex. Four representative mesocortex markers-Crym, Lypd1, Cdh13, and Smoc2-are amply illustrated, jointly with complementary material including myelin basic protein, to check myelination, and Rorb, to check layer 4 presence. The retrosplenial (ReSp) area, long held to be mesocortical, does not share any of the 46 markers of mesocortex and instead expresses Nr4a2 and Tshz2, selective parahippocampal allocortex markers. Moreover, it is not hypomyelinic and lacks a Rorb-positive layer 4, aspects generally present in mesocortex. Exclusion of the ReSp area from the mesocortex ring reveals the latter to be closed at this locus instead by two adjacent areas previously thought to be associative visual ICx (reidentified here molecularly as postsplenial and parasplenial mesocortex areas). The concepts of ICx, mesocortex, and parahippocampal allocortex are thus subtly modified by substantial molecular evidence.

Medial Amygdalar Tau Is Associated With Mood Symptoms in Preclinical Alzheimer’s Disease

BackgroundWhile the amygdala receives early tau deposition in Alzheimer’s disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms. MethodsWe examined 598 individuals (347 amyloid positive [58% female], 251 amyloid negative [62% female] subset in tau positron emission tomography and functional magnetic resonance imaging cohorts) from the A4 (Anti-Amyloid Treatment in Asymptomatic AD) Study. In the tau positron emission tomography cohort, we used amygdalar segmentations to examine representative nuclei from 3 functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the functional magnetic resonance imaging cohort. Finally, we conducted exploratory post hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores. ResultsAmyloid-positive individuals demonstrated increased tau binding in the medial and lateral amygdala, and tau binding in these regions was associated with mood symptoms. Across amygdalar divisions, amyloid-positive individuals had relatively higher regional connectivity from the amygdala to other temporal regions, the insula, and the orbitofrontal cortex, but medial amygdala to retrosplenial cortex connectivity was lower. Medial amygdala to retrosplenial connectivity was negatively associated with anxiety symptoms, as was retrosplenial tau. ConclusionsOur findings suggest that preclinical tau deposition in the amygdala and associated changes in functional connectivity may be related to early mood symptoms in AD.

Integrity of neural extracellular matrix is required for microglia-mediated synaptic remodeling.

Microglia continuously remodel synapses, which are embedded in the extracellular matrix (ECM). However, the mechanisms, which govern this process remain elusive. To investigate the influence of the neural ECM in synaptic remodeling by microglia, we disrupted ECM integrity by injection of chondroitinase ABC (ChABC) into the retrosplenial cortex of healthy adult mice. Using in vivo two-photon microscopy we found that ChABC treatment increased microglial branching complexity and ECM phagocytic capacity and decreased spine elimination rate under basal conditions. Moreover, ECM attenuation largely prevented synaptic remodeling following synaptic stress induced by photodamage of single synaptic elements. These changes were associated with less stable and smaller microglial contacts at the synaptic damage sites, diminished deposition of calreticulin and complement proteins C1q and C3 at synapses and impaired expression of microglial CR3 receptor. Thus, our findings provide novel insights into the function of the neural ECM in deposition of complement proteins and synaptic remodeling by microglia.

Hierarchical Gradients of Encoded Spatial and Sensory Information in the Neocortex Are Attenuated by Dorsal Hippocampal Lesions.

During navigation, the neocortex actively integrates learned spatial context with current sensory experience to guide behaviors. However, the relative encoding of spatial and sensorimotor information among cortical cells, and whether hippocampal feedback continues to modify these properties after learning, remains poorly understood. Thus, two-photon microscopy of male and female Thy1-GCaMP6s mice was used to longitudinally image neurons spanning superficial retrosplenial cortex and layers II-Va of primary and secondary motor cortices before and after bilateral dorsal hippocampal lesions. During behavior on a familiar cued treadmill, the locations of two obstacles were interchanged to decouple place-tuning from cue-tuning among position-correlated cells with fields at those locations. Subpopulations of place and cue cells each formed interareal gradients such that higher-level cortical regions exhibited higher fractions of place cells, whereas lower-level regions exhibited higher fractions of cue cells. Position-correlated cells in the motor cortex also formed translaminar gradients; more superficial cells were more likely to exhibit fields and were more sparsely and precisely tuned than deeper cells. After dorsal hippocampal lesions, a neural representation of the learned environment persisted, but retrosplenial cortex exhibited significantly increased cue-tuning, and, in motor cortices, both position-correlated cell recruitment and population activity at the unstable obstacle locations became more homogeneously elevated across laminae. Altogether, these results support that the hippocampus continues to modulate cortical responses in familiar environments, and the relative impact of descending feedback obeys hierarchical interareal and interlaminar gradients opposite to the flow of ascending sensory inputs.

Retrosplenial cortex and aversive conditioning.

The retrosplenial cortex (RSC) is well-known for its contribution to episodic memory, as well as contextual and spatial learning and memory. However, two literatures have also emerged examining the role of the RSC in aversive conditioning. The purpose of this manuscript is to review, and attempt to integrate, these two literatures. We focus on studies in which discrete cues, such as tones, predict the occurrence of aversive outcomes, such as mild shocks. Using both electrophysiological recordings and lesion methods, the first literature has examined RSC contributions to discriminative avoidance conditioning. The second, and more recent literature, has focused on the role of the RSC in Pavlovian fear conditioning. We discuss both literatures in terms of the type of information processed by the RSC, the role of the RSC in memory storage, and how the aversive conditioning literature might be consistent with a role for the RSC in contextual learning and memory.