Retrosplenial Cortex Research Articles

Functional connectivity linking the hippocampus, retrosplenial, and orbitofrontal cortex correlates with increased seizure severity in temporal lobe epilepsy.

The persistence of drug memories accounts for the high risk of drug relapse, which is a major challenge in the treatment of substance use disorders. However, the neurobiological underpinnings, especially the dynamic changes of brain networks underlying long-term drug memories, remain unclear. Here we utilized cocaine conditioned place preference (CPP) in rats combined with c-Fos mapping in multiple brain regions and network analysis to assess dynamic patterns of neural activity and functional memory networks following the recall of short-term and long-term cocaine memory. Furthermore, we employed chemogenetic interventions to disrupt the core nodes within the long-term memory network. Our results showed that the recall of long-term cocaine memory is characterized by more extensive and stronger neuronal activation, greater interregional co-activation, and a more coordinated and stable brain network, compared to short-term cocaine memory. Within this reorganized network, the retrosplenial cortex (RSC) emerged as a key hub. Chronic inhibition of RSC disrupted the network and impaired the recall of the long-term memory. These findings demonstrate that the persistence of cocaine memory is encoded by a large-scale reorganization toward a more integrated and stable brain state, and identify the RSC as a critical cortical node orchestrating this process, offering a potential target for relapse prevention strategies.

Understanding how circuits in the brain simultaneously coordinate their activity to mediate complex ethologically 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 (FOV), 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 millimeter × 2.55 millimeter FOV. Cumulatively, the mini-MCAM images over a 30–square millimeter area of sparsely expressed GCaMP6s neurons that were 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 (Ca2+) imaging using the mini-MCAM in both head-fixed and freely behaving mice.

Sex-specific factors and APOEε4 genotype alter functional connectivity at middle age.

IntroductionSpatial memory supports orientation and navigation by integrating multiple spatial reference frames. Neuroimaging and lesion studies implicate the hippocampus (HIP) and retrosplenial cortex (RSC), but causal evidence from non-invasive brain stimulation is limited.MethodsEighteen participants performed a spatial localization task in a virtual room under three stimulation conditions: anodal transcranial direct current stimulation (tDCS) over the left RSC, anodal tDCS over the left HIP, and sham. Task conditions varied in reference frame (viewer-, object-, room-centered) and perspective shift (0°, 45°, 135°). Accuracy was analyzed with non-parametric statistics.ResultsPerformance declined with increasing viewpoint rotation, especially in room-centered trials. RSC stimulation selectively reduced accuracy in room-centered trials with large perspective shifts (135°), whereas HIP stimulation did not significantly modulate performance.DiscussionFindings provide causal evidence for the involvement of the RSC in viewpoint-invariant spatial updating, supporting its role in integrating stable environmental cues. HIP stimulation yielded no reliable behavioral effects, suggesting functional specificity of the RSC and highlighting the challenges of modulating deep cortical structures with tDCS.

Resting-state functional connectivity of the default mode network subsystems as a potential biomarker for delusions in patients with first-episode drug-naïve schizophrenia.

The granular retrosplenial cortex (RSG) supports memory, orientation, and fear processing. The mouse RSG contains several cell types that are remarkably distinct from those found in other cortical regions, including low rheobase neurons that dominate layer 2/3 (L2/3 LR) and similarly exclusive pyramidal cells in layer 5a (L5a RSG). While the functions of the RSG are extensively studied in both mice and rats, it remains unknown if the transcriptomically unique cell types of the mouse RSG are evolutionarily conserved in rats. Here, we show that mouse and rat RSG contain the same unique cell types, with L2/3 LR and L5a RSG cell types together representing more than 50% of all RSG neurons in each species. This preservation of cell types in male and female rats happens despite dramatic changes in key cell-type-specific marker genes, with the Scnn1a expression that selectively tags mouse L5a RSG neurons completely absent in rats. Important for Cre-driver line development, we identify alternative, cross-species genes that can be used to selectively target the cell types of the RSG in both mice and rats. Our results show that the unique cell types of the RSG are conserved across millions of years of evolution and emphasize stark species-specific differences in marker genes that need to be considered when making cell-type-specific knock-in lines across species.Significance statement The retrosplenial cortex is important for memory, spatial orientation, fear processing, and imagining oneself in the future. Lesions to this brain region in humans lead to an inability to find one's way home. The mouse granular retrosplenial cortex (RSG) contains neuron types that are particularly distinct from those found in neighboring regions. Whether these distinct neurons are preserved across species remains unknown. Here, we show that all cell types of the mouse RSG are also found in rats, and the unique RSG cell types dominate the region in each species. These results suggest that the unique RSG neurons support evolutionarily important functions that facilitate the preservation of these neurons across millions of years of evolution.

Target- and state-dependent information flow of hippocampal ripples to the neocortex during slow wave activity.

Corticolimbic activation patterns during aversive audiogenic stress assessed by cerebral perfusion using [99mTc]HMPAO SPECT/CT.

The Adolescent functional connectome is dynamically controlled by a sparse core of cognitive and topological hubs.

Humans can perceive their relative position to the goal according to distal landmark cues (DLCs), which are cues situated in the distance and beyond the navigation scope. Specifically, familiar DLCs can facilitate the accuracy of spatial representations in human navigation. It is still unclear how human brain infers the distance and direction deviation to the goal through familiar DLCs. To address this question, we invited 26 young healthy adults to learn the locations of eight objects in a virtual reality arena with DLCs. We used two metrics: Euclidean distance (ED) for measuring distance and minimal angle (MA) for measuring direction. We then tested their direction and distance memory in the previous arena with familiar DLCs during fMRI scanning and in a different arena with unfamiliar DLCs. We performed a moderation analysis, which showed that the DLCs' familiarity moderated the influence of the ED to the goals (EDg) on end point location error evaluated by the ED (EDe). A univariate analysis on the task-fMRI data showed that the right SMA was related to the modulation of DLCs' familiarity on the relationship between EDg and EDe. Multivariate analyses on the fMRI data showed that the parahippocampal gyrus and retrosplenial cortex represented EDg in the direction memory retrieval, whereas thalamus and OFC represented both EDg and MA deviation from the goal (MAg) in the distance memory retrieval. These results provide insights into the neural mechanisms for the enhancement of DLCs in encoding relative position from the goal in spatial navigation.

Classical psychedelic drugs show promise as a treatment for major depressive disorder and related psychiatric disorders. This therapeutic efficacy stems from long-lasting psychedelic-induced neuroplasticity onto prefrontal cortical neurons and is thought to require the postsynaptic expression of serotonin 2A receptors (5-HT2AR). However, other cortical regions such as the granular retrosplenial cortex (RSG) - important for memory, spatial orientation, fear extinction, and imagining oneself in the future, but impaired in Alzheimer's disease - lack 5-HT2AR and are thus considered unlikely to benefit from psychedelic therapy. Here, we show that RSG pyramidal cells lacking postsynaptic 5-HT2A receptors still undergo long-lasting psychedelic-induced synaptic enhancement. A newly engineered CRISPR-Cas-based conditional knockout mouse line reveals that this form of psychedelic-induced retrosplenial plasticity requires presynaptic 5-HT2A receptors expressed on anterior thalamic axonal inputs to RSG. These results highlight a broader psychedelic therapeutic utility than currently appreciated, suggesting potential for augmenting RSG circuit function in Alzheimer's disease, post-traumatic stress disorder, and other neuropsychiatric conditions, despite the lack of postsynaptic 5-HT2A receptors.

Impairments of episodic memory, the capacity to remember and re-live details from one’s past, are common across mental illnesses, but are particularly severe in those with late adolescent onset, such as schizophrenia and major depression. Using mice, we demonstrate that during late adolescence, the retrosplenial cortex (RSP), an established hub of episodic memory and default mode networks, undergoes extensive reorganization, interfering with memory functions and potentially increasing vulnerability to these illnesses. Specifically, we demonstrated that the levels of perineuronal nets (PNN), key PNN constituents, and parvalbumin-positive (PVALB) interneurons established during early adolescence (p30), significantly declined by late adolescence(p60–75). Using context fear conditioning (CFC), we found that these structural, molecular, and cellular changes facilitated the formation of long-lasting and context-specific memories, but at the expense of memories acquired during early adolescence. Interestingly, early adolescent memories spontaneously recovered by middle adulthood but lost context specificity. The observed neurobiological and behavioral changes were attenuated by stabilizing PNN, and exacerbated by disrupting PNN, suggesting that PVALB neuron loss and memory expression deficits were secondary to PNN degradation. These findings showed that despite its superior performance during early adolescence relative to early life, the RSP memory circuit does not show full cortical maturity until late adolescence. In susceptible individuals, the observed dynamics of the extracellular matrix and PVALB neurons could interact with genetic factors, increasing risk for the development of late adolescent psychopathologies.

BackgroundThe relationship between blood pressure (BP) trajectories across early (∼40 years) into mid-life (∼55 years) and preclinical dementia has not previously been well studied using positron emission tomography (PET) imaging outcomes.ObjectiveTo examine the association between BP trajectories across early mid-life into mid mid-life and amyloid- and tau-PET burden in adults without clinical dementia.MethodsThis prospective cohort study included dementia-free Framingham Heart Study 3rd generation participants with data on remote BP (2002-2005) and recent BP (2016-2019) who participated in 11C-Pittsburgh Compound-B (PiB)-PET and/or 18F-Flortaucipir (FTP)-PET scans between 2016 to 2022. Outcomes included global amyloid deposition (in the frontal, lateral temporal, parietal and retrosplenial cortices, FLR region) and entorhinal tau deposition.ResultsIn 410 participants (mean age 40 ± 8 years at remote exam, 56 ± 8 years recent exam), the mean time between the remote exam BP measurement and PET was 16 ± 2 years. A steep change (slope of ≥0.5 or ≤-0.5 mmHg/year) in DBP over early to mid-life was associated with increased entorhinal tau-PET deposition (β = 0.02; 95% CI = 0.01, 0.04; p = 0.047), driven by a steep decline in DBP (β = 0.04; 95% CI = 0.01, 0.07; p = 0.01). Persistent hypertension, new-onset hypertension, resolved hypertension or a steep change in SBP were not associated with amyloid or tau burden.ConclusionsIn adults without clinical dementia, a steep DBP decline from early mid-life into mid-life was associated with tau deposition in the entorhinal cortex, one of the earliest affected regions in Alzheimer's disease. Maintaining normotension across the ∼15-16 years mid-life period may reduce the future risk of tau-PET burden in the brain.

Dynamic changes in orbitofrontal-hippocampal connectivity linked to cognitive map formation in humans.

This study investigated the learning strategy preferences of 11-month-old APP/PS1 double transgenic (Tg) mice, a well-established murine model of Alzheimer’s disease (AD). APP/PS1 Tg and non-Tg control mice were serially trained in visual and hidden platform tasks in the Morris water maze. APP/PS1 Tg mice performed poorly in visual platform training compared with non-Tg mice but performed as well as non-Tg mice in hidden platform training. Further analysis of their search paths for locating a hidden platform revealed that APP/PS1 Tg mice used more cued/response search patterns than place/spatial search patterns compared with non-Tg mice. Three months later, the object/location recognition memory of APP/PS1 Tg mice was assessed. Although their object recognition memory was intact, their object location memory was impaired. Neuropathological AD features of APP/PS1 transgenic mice were observed in the medial prefrontal cortex, retrosplenial cortex, and hippocampus, key brain regions involved in learning strategy shifts and spatial cognition. These results indicate that distinct search patterns and spatial memory deficits in APP/PS1 Tg mice are key features of AD animal models.

The precuneus is a central hub of the human brain, and its morphology displays a noticeable individual variability. It is larger in humans than in other primates, and it is affected by atrophy and hypometabolism in the early stages of Alzheimer's disease (AD). In this study, we compare its general morphology in normal aging subjects and AD patients, considering its geometry through shape analysis, and the atrophy at its boundary by quantifying the intersulcal spacing. Results suggest that the AD sample displays a reduction of the inferior regions of the precuneus, namely those that fade into the posterior cingulate and retrosplenial cortex. During aging, sulcal spacing is pronounced at the superior and posterior regions, although in the AD sample the latter change is more marked. However, these differences are associated with a remarkable individual variation and a consistent overlap between group ranges. This study stresses further the differences between the dorsal and ventral regions of the precuneus. Beyond functional factors, the dorsal areas represent a region of scarce spatial constraints, whereas the ventral regions are embedded in a complex topological environment. This structural difference must be considered when investigating cortical morphology in both normal and pathological conditions.

The dorsal midline thalamus (DMT) is composed of the paraventricular (PV) and paratenial (PT) nuclei. While the anatomical and functional properties of PV are well-established, PT has remarkably received very little attention-even though the efferent projections of PV and PT are very similar. Using a combination of retrograde tracing and immunohistochemistry, we examined the anatomical inputs to PT and compared them with those to the anterior and posterior PV and to the anterodorsal nucleus of the thalamus. In addition, we examined orexinergic and serotonergic afferents to the PT, comparing them with those to other thalamic nuclei. We found that PT and PV receive input from a common set of structures, including the orbitomedial prefrontal cortex, nuclei of the diagonal band, septum, subiculum of the hippocampus, bed nucleus of the stria terminalis, hypothalamus, reticular nucleus of the thalamus, dorsal raphe nucleus, and periaqueductal gray. However, the pattern and density of these various afferents to PT and PV significantly differed. For instance, PT received much stronger inputs from the orbitofrontal cortex, while PV received stronger projections from the subiculum of the hippocampus and more widespread input from the hypothalamus and the brainstem. By comparison, afferents to AD differed from PT (and PV), as AD received substantial input from the retrosplenial and anterior cingulate cortices, and uniquely from the lateral mammillary nucleus. Further, orexinergic (ORX) and serotonergic (5-HT) fibers distributed at best modestly to PT, which contrasted with quite dense ORX and 5-HT innervation of PV. The present findings, essentially representing the first comprehensive examination of afferent projections to PT, show that the inputs to PT mainly arise from limbic forebrain structures-with pronounced projections from the orbitofrontal cortex, nuclei of the diagonal band, and the reticular nucleus of the thalamus. The functional properties of PT partially overlap with those of PV, but as described herein PT also participates in unique affective, cognitive, and motivational behaviors.

Working memory allows us to keep information in memory for the time needed to perform a given task. Such fundamental cognitive ability relies on a neural circuit, including the retrosplenial cortex (RSC), connected to several cortical areas, functionally and anatomically, namely primary visual areas, and higher cognitive areas such as the cingulate, midcingulate, and subicular cortices. RSC bears intimate anatomical and functional connections with the hippocampus and has been implicated in integrating and translating spatial-temporal contextual information between ego- and allocentric reference frames to compute predictions about goals in goal-directed behaviors. The relative contribution of the hippocampus and retrosplenial cortex in working memory-guided behaviors remains unclear due to the lack of studies reversibly interfering with synapses connecting the two regions during such behaviors. We here used eArch3.0, a hyperpolarizing proton pump, to silence hippocampal axon terminals in RSC while animals perform a standard delayed non-match to place task. We found that such manipulation impairs memory retrieval, significantly decreasing performance and hastening decision-making. Furthermore, we found that such impairment outlasts light activation of the opsin, its effects being noticed up to three subsequent trials.

Cognitive reappraisal and attentional distraction constitute two core strategies for regulating emotions. Prior studies have largely focused on young adults regulating simple laboratory stimuli, with few direct comparisons of brain regions that differentiate or mutually implement these strategies. Here, we expanded the typical age range of participants, compared reappraisal and distraction within participants, and used ecologically valid autobiographical memories as regulatory targets. Sixty-two healthy adults aged 35-75 years generated cue words for negative and neutral autobiographical memories and were trained to either reappraise, distract, or let their emotions flow naturally in response to cued memories. Strategy-specific contrasts were derived from whole-brain fMRI data using univariate analyses. For reappraisal, relative to flow, we observed activity in bilateral occipital cortex, right cerebellum, and cingulate cortex and primarily left-sided frontal, temporal, and parietal cortices. Distraction, relative to flow, engaged bilateral lateral prefrontal, medial parietal, cingulate, occipital, and retrosplenial regions and left cerebellum. Common areas of activation included midline occipital and posterior cingulate cortices. Direct comparisons yielded strategy differences across multiple cortical areas: distraction engaged paralimbic areas (insula and left parahippocampal gyrus), dorsolateral and ventrolateral pFC, and right inferior frontoparietal cortex, whereas reappraisal engaged dorsomedial pFC, left ventrolateral pFC, anterior temporal cortex, and left posterolateral pFC. In-scanner valence ratings verified the efficacy of the experimental manipulation and revealed a negative impact of age on reappraisal success, which was correlated with greater visual cortical processing. These findings extend knowledge regarding the neural mechanisms of emotion regulation across the adult lifespan for autobiographical events.