Retrosplenial Cortex Research Articles

Spatial mapping of activity changes across sensory areas following visual deprivation in adults.

Loss of a sensory modality triggers global adaptation across brain areas, allowing the remaining senses to guide behavior more effectively. There are specific synaptic and circuit plasticity observed across many sensory areas, which suggests potential widespread changes in activity. Here we used a cFosTRAP2 mouse line to drive tdTomato (tdT) expression in active cells to spatially map the extent of activity changes in various sensory areas in adult mice of both sexes following two modes of visual deprivation. We found that in the primary visual cortex (V1) both dark exposure (DE) and enucleation (EN) caused an initial loss of active cells followed by a partial rebound, which occurred relatively more in the superficial layers. A similar pattern was observed in the secondary visual cortex, especially in the lateral areas (V2L). The spared primary sensory cortices adapted distinctly. In the primary somatosensory barrel cortex (S1BF) there was a change in the density of active cells dependent on the duration and the mode of visual deprivation. In the primary auditory cortex (A1), there was a relative reduction in the density of active cells in the superficial layers without a significant change in the overall density. There were minimal changes in the active cell density in the secondary cortices of the spared senses and the multisensory retrosplenial cortex (RSP). Our results are consistent with cross-modal recruitment of the deprived visual cortex and compensatory plasticity in the spared primary sensory cortices that can support enhanced processing and refinement of the spared senses.Significance Statement The neural basis for improved processing of the spared senses after losing vision is largely dependent on plasticity mechanisms driven by neural activity. Using a transgenic mouse model to label active neurons in a temporally controlled manner, this study reveals the spatial pattern of widespread activity changes across brain areas following visual deprivation in adult mice. The findings suggest that the deprived visual cortex undergoes an initial reduction in activity followed by a rebound suggestive of cross-modal recruitment. Activity changes in the spared primary sensory cortices conform to compensatory plasticity, which could support improved processing of the spared senses. The results highlight the presence of large-scale plasticity in the adult brain to compensate for loss of vision.

Histamine-tuned subicular circuit mediates alert-driven accelerated locomotion in mice

The locomotive action involves diverse coordination, necessitating the integration of multiple motor neural circuits. However, the precise circuitry mechanism governing emotion-driven accelerated locomotion remains predominantly elusive. Here we dissect projections from the tuberomammillary nucleus (TMN) to subiculum (SUB) which promote alert-driven accelerated locomotion. We find that TMN histaminergic neurons respond to high-speed locomotion in both natural and alert acceleration. The TMN-SUB circuit is sufficient but not essential for amplifying accelerated locomotion from low to high-speed movement in basal condition, but it is both sufficient and necessary in alert condition for modulating accelerated locomotion during high-speed escape behavior. TMN histaminergic neuron activates SUB glutamatergic “fast locomotor cell” that projects to retrosplenial granular cortex (RSG) mainly through histamine H2 receptor (H2R). This study reveals the critical role of the histamine-tuned SUB circuit in alert-driven accelerated locomotion in mice, providing a theoretical foundation for comprehending neural circuit mechanisms of instinctive behaviors under alert.

Mapping of c-Fos Expression in Rat Brain Sub/Regions Following Chronic Social Isolation: Effective Treatments of Olanzapine, Clozapine or Fluoxetine.

The c-Fos as a marker of cell activation is used to identify brain regions involved in stimuli processing. This review summarizes a pattern of c-Fos immunoreactivity and the overlapping brain sub/regions which may provide hints for the identification of neural circuits that underlie depressive- and anxiety-like behaviors of adult male rats following three and six weeks of chronic social isolation (CSIS), relative to controls, as well as the antipsychotic-like effects of olanzapine (Olz), and clozapine (Clz), and the antidepressant-like effect of fluoxetine (Flx) in CSIS relative to CSIS alone. Additionally, drug-treated controls relative to control rats were also characterized. The overlapping rat brain sub/regions with increased expression of c-Fos immunoreactivity following three or six weeks of CSIS were the retrosplenial granular cortex, c subregion, retrosplenial dysgranular cortex, dorsal dentate gyrus, paraventricular nucleus of the thalamus (posterior part, PVP), lateral/basolateral (LA/BL) complex of the amygdala, caudate putamen, and nucleus accumbens shell. Increased activity of the nucleus accumbens core following exposure of CSIS rats either to Olz, Clz, and Flx treatments was found, whereas these treatments in controls activated the LA/BL complex of the amygdala and PVP. We also outline sub/regions that might represent potential neuroanatomical targets for the aforementioned antipsychotics or antidepressant treatments.

Contextual Fear Conditioning Uncovers Spine and Learning Deficits in the Retrosplenial Cortex in a Familial Alzheimer’s Disease Mouse Model

While excitatory synapse loss is documented in the brains of Alzheimer’s Disease (AD) patients, its role in episodic learning decline, one of the first evident AD symptoms, is unclear. The retrosplenial cortex (RSC), a cortical structure required for episodic learning, provides an ideal entry point to study the role of synapse loss in cognitive decline in AD since it is a site of high amyloid load and dysfunctional early in AD progression. Further, excitatory synapse assembly, both turnover and clustered synapse formation, is highly correlated with episodic learning performance in the RSC. We hypothesize alterations in synapse assembly in the RSC of AD patients contribute to early cognitive decline in the disease. To address this hypothesis, we examined both excitatory synapse density in the RSC and contextual learning in a familial AD (fAD) mouse model, an early onset amyloid model of AD. Importantly, we find age-dependent excitatory synapse loss in the RSC of fAD mice, as measured by imaging and quantification of GFP-labeled dendritic spines. Further, prior to frank spine loss in 5-month-old fAD mice we found episodic learning deficits, as measured by contextual fear conditioning (CFC). Using this early time point, we examined spine dynamics in vivo with MP imaging in the RSC of fAD mice or controls while engaged in CFC learning. Interestingly, we find deficits both in spine turnover and clustered spine formation and a loss of correlations of these spine metrics with CFC performance, suggesting aberrant spine dynamics may be causal in episodic learning deficits in this AD model, consistent with our hypothesis. Future studies will pharmacologically target these aberrant spine dynamics in fAD mice in an effort to strengthen the causal link between alterations in synapse assembly and cognitive decline in AD as well as provide potential therapeutic approaches to reverse early stages of the disease.

CNSC-64. BEYOND THE LOCAL TUMOR MICROENVIRONMENT: CHARACTERIZING CHANGES TO NEURONAL ACTIVITY INDUCED BY PEDIATRIC HIGH-GRADE GLIOMA

Abstract Bidirectional electrochemical signaling between neurons and tumor cells is emerging as a critical regulator of pediatric high-grade glioma (HGG) pathology. Neuron-tumor interactions are known to induce local neuronal hyperactivity. However, recent work tracing the projections of these neuron-tumor networks revealed that HGG neuronal recruitment extends beyond the local tumor microenvironment (TME). These findings suggest that tumor-induced hyperexcitability may spread beyond the local TME and drive brain-wide circuit-level changes. To elucidate how non-tumor innervated brain regions are affected by TME hyperactivity we first characterized neuronal hyperactivity induced by a cortical patient-derived pediatric high-grade cell line in vitro on human iPSC-derived neurons. In vitro calcium imaging experiments demonstrated an increase in the number of calcium fluctuations in glioma co-cultured neurons. In parallel, multi-electrode recordings revealed increased population spiking activity and amplitude in neurons co-cultured with glioma cells. We then xenografted these HGG cells into the prefrontal cortex of mice and performed whole brain-clearing and cFos staining on tumor-bearing vs saline-injected control samples. As cFos is an immediate early gene activated by neuronal activity, we utilized the density of cFos expression as a readout-out of neuronal activation in our atlas-aligned segmented brain section analyses. We expectedly observed increased cFos expression within the ipsilateral primary and secondary motor region, which collectively comprise the local TME. Interestingly, we additionally observed elevated cFos in non-tumor bearing brain regions on both the ipsilateral and contralateral hemispheres, largely in layer 2/3 cortical neurons. These neurons form extensive cortico-cortical projections, and we coincidingly observed increased cFos expression in known cortical projection targets of the prefrontal xenograft location, such as somatosensory, visual, and retrosplenial cortices. Our findings suggest that tumor-induced neuronal hyperactivity extends beyond the local TME in a brain-wide manner and potentially follows established neuronal circuits, rendering these connected regions vulnerable to alterations in neuronal activity.

Projection-specific circuits of retrosplenial cortex with differential contributions to spatial cognition.

Retrosplenial cortex (RSC) is a brain region involved in neuropsychiatric and neurodegenerative disorders. It has reciprocal connections with a diverse set of cortical and subcortical brain regions, but the afferent structure and behavioral function of circuits defined by its projection-specific sub-populations have yet to be determined. The corticocortical connections between RSC and secondary motor cortex (M2), as well as corticothalamic connections between RSC and anterodorsal thalamus (AD) have been hypothesized to function as semi-independent, but parallel pathways that impact spatial information processing in distinct ways. We used retrograde and anterograde viral tracers and monosynaptic retrograde rabies virus to quantitatively characterize and compare the afferent and efferent distributions of retrosplenial neuron sub-populations projecting to M2 and AD. AD-projecting and M2-projecting RSC neurons overlap in their collateral projections to other brain regions, but not in their projections to M2 and AD, respectively. Compared with AD-projecting RSC neurons, M2-projecting RSC neurons received much greater afferent input from the dorsal subiculum, AD, lateral dorsal and lateral posterior thalamus, and somatosensory cortex. AD-projecting RSC neurons received greater input from the anterior cingulate cortex and medial septum. We performed chemogenetic inhibition of M2- and AD-projecting RSC neurons and examined its impact on object-location memory, object-recognition, open-field exploration, and place-action association. Our findings indicate that inhibition of M2-projecting RSC neurons impairs object location memory as well as place-action association, while the RSC to AD pathway impacts only object-location memory. The findings indicate that RSC is composed of semi-independent circuits distinguishable by their afferent/efferent distributions and differing in the cognitive functions to which they contribute.

The retrosplenial cortical role in delayed spatial alternation

The retrosplenial cortex (RSC) plays an important role in spatial cognition. RSC neurons exhibit a variety of spatial firing patterns and lesion studies have found that the RSC is necessary for spatial working memory tasks. However, little is known about how RSC neurons might encode spatial memory during a delay period. In the present study, we trained control rats and rats with excitotoxic lesions of the RSC on spatial alternation task with varying delay durations and in a separate group of rats, we recorded RSC neuronal activity as the rats performed the alternation task. We found that RSC lesions significantly impaired alternation performance, particularly at the longest delay duration. We also found that RSC neurons exhibited reliably different firing patterns throughout the delay periods preceding left and right trials, consistent with a working memory signal. These differential firing patterns were absent during the delay periods preceding errors. We also found that many RSC neurons exhibit a large spike in firing rate leading up to the start of the trial. Many of these trial start responses also differentiated left and right trials, suggesting that they could play a role in priming the ‘go left’ or ‘go right’ behavioral responses. Our results suggest that these firing patterns represent critical memory information that underlies the RSC role in spatial working memory.

Neuroglia markers expression in the cingulate and retrosplenial cortex of mice after nonseptic dose of lipopolysaccharide

Aim. To study the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1) in the cerebral cingulate and retrosplenial cortex of mice on Day 5 after intraperitoneal (i.p.) administration of bacterial lipopolysaccharide (LPS) at the dose with no nervous tissue inflammation provoked.Materials and methods. The work was performed on 10 female C57BL/6 mice aged 90 ± 3 days. At the same time for 4 days, animals of group 1 were intraperitoneally injected with saline (0.9% NaCl), and animals of group 2 were injected with E. coli LPS endotoxin at a dose of 1 mg/kg/day. On the fifth day, the mice were withdrawn from the experiment by decapitation with xylazine/tiletamine-zoletil premedication, after which histological preparations of the cingulate and retrosplenial cortex were made, stained with antibodies to GFAP and Iba1, and the number of: (1) GFAP-positive cells of cytoplasmic areas, (2) cells with a positive reaction of antibodies to Iba1 were counted using QuPath software. Groups were compared using Mann-Whitney U-test.Results. The number of GFAP-positive cells after LPS administration in Group 2 was significantly higher than in Group 1, exactly 22.5 (8.0; 32.0) vs 9.0 (4.3; 17.0), respectively, p = 0.0038. The number of Iba1-positive portions of cytoplasm also was significantly higher in Group 2, namely 207,5 (154,8; 295,8) vs 128 (89,3; 165,5), respectively, p = 0,014. Both groups showed neither signs of inflammation, excessive blood supply nor hemorrhages, as well as no perivascular edema or leukocytic migration.Conclusion. LPS, administered i.p. to mice at a dose of 1 mg/kg/day for 4 days, allows assessment of changes in glia of CNS in damage with no signs of inflammation there. In cerebral cingulate and retrosplenial cortex, the number of astrocytes with a positive reaction of antibodies to GFAP increases, as well as number macrophages with the expression of the Iba1 protein.

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.

Retrosplenial hypometabolism precedes the conversion from mild cognitive impairment to Alzheimer's disease.

Not all individuals who experience mild cognitive impairment (MCI) transition through progressive stages of cognitive decline at the same rate, if at all. Previous observational studies have identified the retrosplenial cortex (RSC) as an early site of hypometabolism in MCI which seems to be predictive of later transition to Alzheimer's disease (AD). We examined N=399 MCI subjects with baseline 18F-fluorodeoxyglucose positron emission tomography. Subjects were classified based on whether their diagnosis converted from MCI to AD. Whole-brain metabolism was decreased in converters (MCI-AD). This effect was more prominent at the RSC, where MCI-AD subjects showed even greater hypometabolism. Observations of RSC hypometabolism and its utility in predicting transition from MCI-AD withstood statistical analyses in a large retrospective study. These results point to the utility of incorporating RSC hypometabolism into predictive models of AD progression risk and call for further examination of mechanisms underlying this relationship. Not all individuals who develop MCI will progress to AD. Individuals with MCI who progress to AD show early whole-brain hypometabolism. Early hypometabolism is particularly prominent at the RSC.

Topography of putative bidirectional interaction between hippocampal sharp wave ripples and neocortical slow oscillations.

Systems consolidation relies on coordination between hippocampal sharp-wave ripples (SWRs) and neocortical UP/DOWN states during sleep. However, whether this coupling exists across neocortex and the mechanisms enabling it remain unknown. By combining electrophysiology in mouse hippocampus (HPC) and retrosplenial cortex (RSC) with widefield imaging of dorsal neocortex, we found spatially and temporally precise bidirectional hippocampo-neocortical interaction. HPC multi-unit activity and SWR probability was correlated with UP/DOWN states in mouse default mode network, with highest modulation by RSC in deep sleep. Further, some SWRs were preceded by the high rebound excitation accompanying DMN DOWN→UP transitions, while large-amplitude SWRs were often followed by DOWN states originating in RSC. We explain these electrophysiological results with a model in which HPC and RSC are weakly coupled excitable systems capable of bi-directional perturbation and suggest RSC may act as a gateway through which SWRs can perturb downstream cortical regions via cortico-cortical propagation of DOWN states.

Footshock drives remodeling of perineuronal nets in retrosplenial cortex during contextual fear memory formation

The retrosplenial cortex (RSC) plays a critical role in complex cognitive functions such as contextual fear memory formation and consolidation. Perineuronal nets (PNNs) are specialized structures of the extracellular matrix that modulate synaptic plasticity by enwrapping the soma, proximal neurites and synapsis mainly on fast spiking inhibitory GABAergic interneurons that express parvalbumin (PV). PNNs change after contextual fear conditioning (CFC) in amygdala or hippocampus, yet it is unknown if similar remodeling takes place at RSC. Here, we used Wisteria floribunda agglutinin (WFA), a ubiquitous marker of PNNs, to study the remodeling of PNNs in RSC during the acquisition or retrieval of contextual fear conditioning (CFC). Adult male mice were exposed to paired presentations of a context and footshock, or to either of these stimuli alone (control groups). The mere exposure of animals to the footshock, either alone or paired with the context, evoked a significant expansion of PNNs, both in the number of WFA positive neurons and in the area occupied by WFA staining, across the entire RSC. This was not associated with c-Fos expression in RSC nor correlated with c-Fos expression in individual PNNs-expressing neurons in RSC, suggesting that PNNs remodeling is triggered by inputs external to the RSC. We also found that PNNs remodeling was independent of the level of PV expression. Notably, PNNs in RSC remained expanded long-after CFC. These results suggest that, in male mice, the threatening experience is the main cause of PNNs remodeling in the RSC.

Structural diversity inside the mouse subiculum revealed by a new marker protein fibronectin 1.

The subiculum is one of the major output structures of the hippocampal formation and is an important brain region for memory. We have previously reported that the subiculum of rodents can be morphologically divided into its temporal (ventral) two-thirds and the septal (dorsal) third and that the former can be further subdivided into the distal (Sub1) and proximal (Sub2) regions, on a basis of immunohistochemical localizations of several Sub2-specific proteins. However, it remains unclear whether detailed structural organization found in the temporal subiculum is applicable to the septal subiculum. In this study, we found that the distribution of fibronectin (FN1)-positive non-GABAergic, presumptive pyramidal cells exactly coincided with the extent of the Sub1 region of male mice. Using FN1 immunohistochemistry, the Sub1 was found to keep relatively constant size throughout the septotemporal axis of the subiculum. In contrast, the size of the Sub2 became smaller as it approached the septal side, and the Sub2 finally disappeared at the most septal level of the subiculum. Retrograde tracer experiments confirmed that FN1-positive Sub1 neurons projected to the retrosplenial cortex, which is thought to be associated with spatial memory, whereas FN1-negative Sub2 neurons projected to the nucleus accumbens associated with emotional memory. Considering both the functional segregation of these two subicular targets and the relative abundance of the Sub2 on the temporal side, the subiculum can be one of the neural substrates for functional differences between the septal and temporal hippocampal formation associated with the spatial and emotional memory, respectively.

Prophylactic (R,S)-ketamine and (2S,6S)-HNK decrease fear expression by differentially modulating fear neural ensembles

We previously reported that a single injection of (R,S)-ketamine or its metabolite (2S,6S)-hydroxynorketamine (HNK) prior to stress attenuates learned fear. However, whether these drugs attenuate learned fear through divergent or convergent effects on neural activity remains to be determined. 129S6/SvEv male mice were injected with saline, (R,S)-ketamine, or (2S,6S)-HNK one week before a 3-shock contextual fear conditioning (CFC) paradigm. Five days later, mice were re-exposed to the aversive context, and euthanized one hour later to quantify active cells. Brains were processed for c-fos immunoreactivity, and neural networks were built with a novel, wide-scale imaging pipeline. We found that (R,S)-ketamine and (2S,6S)-HNK attenuate learned fear. Fear-related neural activity was altered in: dorsal CA3 following (2S,6S)-HNK; ventral CA3 and CA1, infralimbic (IL) and prelimbic (PL) regions, insular cortex (IC), retrosplenial cortex (RSP), piriform cortex (PIR), nucleus reuniens (RE), and periaqueductal grey (PAG) following both (R,S)-ketamine and (2S,6S)-HNK; and in the paraventricular nucleus of thalamus (PVT) following (R,S)-ketamine. Dorsal CA3 and ventral hippocampus activation correlated with freezing in the (R,S)-ketamine group, and RSP activation correlated with freezing in both (R,S)-ketamine and (2S,6S)-HNK groups. (R,S)-ketamine increased connectivity between cortical and subcortical regions while (2S,6S)-HNK increased connectivity within these regions. This work identifies novel nodes in fear networks, involving the RE, PIR, IC, PAG and RSP, that can be targeted with neuromodulatory strategies or pharmaceutical compounds to treat fear-induced disorders. This approach could be used to optimize target engagement and dosing strategies of existing medications.

Alterations in brain activity and functional connectivity originating residual inhibition of tinnitus induced by tailor-made notched music training.

Tinnitus arises from the intricate interplay of multiple, parallel but overlapping networks, involving at least neuroplastic changes in the auditory and non-auditory activity. Tailor-made notched music training (TMNMT) is a promising therapy for tinnitus. Residual inhibition (RI) is one of the rare interventions capable of temporarily alleviating tinnitus, which is a useful technique that can be applied to tinnitus research and explore tinnitus mechanisms. To our knowledge, this study is the first to investigate the neural mechanisms underlying the RI effect of TMNMT through analysis of neural source activity and functional connectivity of EEG. Forty-four participants with tinnitus were divided into TMNMT group (twenty-two participants; ECnm, NMnm, RInm represent that EEG recordings with eyes closed stimuli-pre, stimuli-ing, stimuli-post by TMNMT music, respectively) and Placebo control group (twenty-two participants; ECpb, PBpb, RIpb represent that EEG recordings with eyes closed stimuli-pre, stimuli-ing, stimuli-post by Placebo music, respectively) in a single-blind manner. Source localization analysis revealed that RI effect of TMNMT significantly increased in current density at the delta band for the insula, subgenual anterior cingulate cortex (sgACC), parahippocampus (PHC), and secondary auditory cortex (AⅡ), and significantly increased in current density at the theta band for the sgACC, and significantly decreased in current density at the alpha band for the precuneus, PHC, primary and secondary auditory cortex (AⅠ and AⅡ). Meanwhile, RI effect of Placebo significantly decreased in current density at the alpha band for the PHC. Functional connectivity analysis demonstrated that RI effect of TMNMT significantly increased in phase coherence between the left AⅡ and the right sgACC; and between the left PHC and the left retrosplenial cortex (RSC) at the theta band. It significantly decreased in phase coherence between the left PHC and the right precuneus, the right posterior cingulate cortex (PCC), the right AⅡ; between the right PHC and the right PCC; and between the right PCC and the right AⅡ at the alpha band. RI effect of Placebo significantly increased in phase coherence between the left insula and the right precuneus, the left PHC, the right PHC, the left AⅠ, the left AⅡ; between the left sgACC and the right PHC; between the left AⅡ and the right PHC, the left PCC at the delta band. It was also found that the current density of sgACC was significant positively correlated with the tinnitus evaluation indicators (Loudness, VAS, THI, TFI) at the alpha band in TMNMT group. These results suggested that TMNMT, a novel music therapy for tinnitus, had a stronger ability of residual inhibition (RI), which RI effect of TMNMT not only participated in the activity of auditory network (AⅠ, AⅡ), but also extends to non-auditory network, particularly higher-level auditory association cortices such as the sgACC, PHC and PCC. The current study provided valuable experimental evidence and practical prospects for the potential applications of TMNMT in tinnitus treatment.

Potential Biomarkers of Dysmenorrhea Relief: A MEG Study of Hinoki Aromatherapy and Working Memory.

Background/Objectives: This study explored the potential of Hinoki aromatherapy to induce biomarkers of dysmenorrhea relief through working memory. Structural magnetic resonance imaging and magnetoencephalography (MEG) were used to examine their effects on neurophysiological responses to a visual working memory (VWM) test. Behavioral performance was measured to understand its effects on the overall working memory. Methods: Twenty-four healthy participants completed the VWM task during nonmenstruation and menstruation. Behavioral (accuracy and reaction time) and neurophysiological (event-related fields, source estimation, and permutation t-test on source data) measures were assessed without and with Hinoki aromatherapy. Results: A significant difference in the ratio of accuracy to reaction time was found without and with aromatherapy in participants with dysmenorrhea, suggesting that aromatherapy may improve working memory performance in this population. MEG analysis revealed high temporal resolution of evoked latency and intensity during the VWM task. Source localization of the activation aimed to identify brain areas involved in dysmenorrhea. Aromatherapy reduced signals in these areas, which may also contribute to reducing dysmenorrhea-related visual signals. Conclusions: Based on these findings, Hinoki aromatherapy may be a promising treatment option for alleviating dysmenorrhea and improving related symptoms by reducing activity in brain pain processing regions. These regions include the left entorhinal cortex, inferior temporal gyrus, primary visual cortex, retrosplenial cortex, and presubiculum. Furthermore, decreased activity in these areas with aromatherapy suggests that they could be used as biomarkers of dysmenorrhea relief.

High-resolution awake mouse fMRI at 14 Tesla.

High-resolution awake mouse fMRI remains challenging despite extensive efforts to address motion-induced artifacts and stress. This study introduces an implantable radiofrequency (RF) surface coil design that minimizes image distortion caused by the air/tissue interface of mouse brains while simultaneously serving as a headpost for fixation during scanning. Furthermore, this study provides a thorough acclimation method used to accustom animals to the MRI environment minimizing motion induced artifacts. Using a 14T scanner, high-resolution fMRI enabled brain-wide functional mapping of visual and vibrissa stimulation at 100×100×200μm resolution with a 2s per frame sampling rate. Besides activated ascending visual and vibrissa pathways, robust BOLD responses were detected in the anterior cingulate cortex upon visual stimulation and spread through the ventral retrosplenial area (VRA) with vibrissa air-puff stimulation, demonstrating higher-order sensory processing in association cortices of awake mice. In particular, the rapid hemodynamic responses in VRA upon vibrissa stimulation showed a strong correlation with the hippocampus, thalamus, and prefrontal cortical areas. Cross-correlation analysis with designated VRA responses revealed early positive BOLD signals at the contralateral barrel cortex (BC) occurring 2 seconds prior to the air-puff in awake mice with repetitive stimulation, which was not detected using a randomized stimulation paradigm. This early BC activation indicated a learned anticipation through the vibrissa system and association cortices in awake mice under continuous training of repetitive air-puff stimulation. This work establishes a high-resolution awake mouse fMRI platform, enabling brain-wide functional mapping of sensory signal processing in higher association cortical areas.

Super-resolution ultrasound imaging reveals temporal cerebrovascular changes with disease progression in female 5×FAD mouse model of Alzheimer's disease: correlation with pathological impairments

Vascular dysfunction is closely associated with the progression of Alzheimer's disease (AD). A critical research gap exists that no studies have explored the invivo temporal changes of cerebrovascular alterations with AD progression in mouse models, encompassing both structure and flow dynamics at micron-scale resolution across the early, middle, and late stages of the disease. In this study, ultrasound localisation microscopy (ULM) was applied to image the cerebrovascular alterations of the transgenic female 5×FAD mouse model across different stages of disease progression: early (4 months), moderate (7 months), and late (12 months). Age-matched non-transgenic (non-Tg) littermates were used as controls. Immunohistology examinations were performed to evaluate the influence of disease progression on the β-amyloid (Aβ) load and microvascular alterations, including morphological changes and the blood-brain barrier (BBB) leakage. Our findings revealed a significant decline in both vascular density and flow velocity in the retrosplenial cortex of 5×FAD mice at an early stage, which subsequently became more pronounced in the visual cortex and hippocampus as the disease progressed. Additionally, we observed a reduction in vascular length preceding diminished flow velocities in cortical penetrating arterioles during the early stages. The quantification of vascular metrics derived from ULM imaging showed significant correlations with those obtained from vascular histological images. Immunofluorescence staining identified early vascular abnormalities in the retrosplenial cortex. As the disease advanced, there was an exacerbation of Aβ accumulation and BBB disruption in a regionally variable manner. The vascular changes observed through ULM imaging exhibited a negative correlation with amyloid load and were associated with the compromise of the BBB integrity. Through high-resolution, invivo imaging of cerebrovasculature, this study reveals significant spatiotemporal dysfunction in cerebrovascular dynamics accompanying disease progression in a mouse model of AD, enhancing our understanding of its pathophysiology. This study is supported by grants from National Key Research and Development Program of China (2020YFA0908800), National Natural Science Foundation of China (12074269, 82272014, 82327804, 62071310), Shenzhen Basic Science Research (20220808185138001, JCYJ20220818095612027, JCYJ20210324093006017), STI 2030-Major Projects (2021ZD0200500) and Guangdong Natural Science Foundation (2024A1515012591, 2024A1515011342).

Unique Transcriptomic Cell Types of the Granular Retrosplenial Cortex are Preserved Across Mice and Rats Despite Dramatic Changes in Key Marker Genes.

The granular retrosplenial cortex (RSG) supports key functions ranging from memory consolidation to spatial navigation. The mouse RSG contains several cell types that are remarkably distinct from those found in other cortical regions. This includes the physiologically and transcriptomically unique low rheobase neuron that is the dominant cell-type in RSG layers 2/3 (L2/3 LR), as well as the similarly exclusive pyramidal cells that comprise much of RSG 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 not only contain the same cell types, but key subtypes including the L2/3 LR and L5a RSG neurons are amplified in their representations in rats compared to mice. 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 evolutionarily conserved across millions of years of evolution between mice and rats, but also emphasize stark species-specific differences in marker genes that need to be considered when making cell-type-specific transgenic lines of mice versus rats.

Distinct codes for environment structure and symmetry in postrhinal and retrosplenial cortices

Complex sensory information arrives in the brain from an animal’s first-person (‘egocentric’) perspective. However, animals can efficiently navigate as if referencing map-like (‘allocentric’) representations. The postrhinal (POR) and retrosplenial (RSC) cortices are thought to mediate between sensory input and internal maps, combining egocentric representations of physical cues with allocentric head direction (HD) information. Here we show that neurons in the POR and RSC of female Long-Evans rats are tuned to distinct but complementary aspects of local space. Egocentric bearing (EB) cells recorded in square and L-shaped environments reveal that RSC cells encode local geometric features, while POR cells encode a more global account of boundary geometry. Additionally, POR HD cells can incorporate egocentric information to fire in two opposite directions with two oppositely placed identical visual landmarks, while only a subset of RSC HD cells possess this property. Entorhinal grid and HD cells exhibit consistently allocentric spatial firing properties. These results reveal significant regional differences in the neural encoding of spatial reference frames.