Hippocampus

Hippocampal place cells encode spatial information within a theta-organized temporal framework paced by the medial septum (MS). Lesions or inactivation of the MS impair spatial learning and disrupt hippocampal theta rhythmicity, long-term potentiation, and plasticity-related gene expression, while often sparing spatially selective firing of CA1 neurons (but not CA3 neurons). Although many rodent studies argue against classical systems consolidation by showing persistent hippocampal dependence of spatial memories, other work has suggested that training structure, spaced vs. massed trials, can influence this dependence. To investigate this possibility, we used DREADD-based, reversible, inhibition of MS GABAergic neurons, some of which are known to project to hippocampus. DREADD activation reduced hippocampal theta power and spatial information encoded by hippocampal neurons while largely preserving overall neuronal firing. We then examined the effect of inhibition of medial septal GABAergic neurons on learning the correct goal arm in an 8-arm maze when the correct arm was randomly changed each day. On each day, the mice were given two forced-choice trials indicating the correct arm and then 5 free-choice trials (without correction) and were always started from an opaque cylinder in the maze center, in a random orientation, to eliminate possible use of a simple response strategy. When the correct goal arm varied randomly daily, MS cell inhibition severely and repeatedly impaired acquisition. In contrast, when the correct goal arm was subsequently fixed across days, performance was initially impaired but became resistant to DREADD activation over time. Once performance reached asymptote, the goal arm was switched to a new (random) position. In this case, learning was no longer impaired by DREADD activation. This generalization suggests that repeated fixed-goal training in the same environment induces a broader reorganization of the neural systems supporting spatial behaviour. One possibility is that mice develop a septal-independent task-solving strategy that supports both retrieval of established goal locations and acquisition of new ones within a stable environment. This transition could reflect the gradual adoption of a non-spatial strategy such as visual pattern recognition, or the use of a directional cue. Moving the most salient distal cue in the environment (a single room light) produced a substantial change in the visual configurations seen from the arm entry points, and disrupted performance; however, it did not produce a consistent directional shift relative to the cue, suggesting that the light contributed to an integrated visuo-spatial representation rather than serving as the reference frame origin. We conclude that the mice switched from a hippocampus/MS-dependent spatial strategy to a non-hippocampus-dependent visual pattern matching solution.

Older adults typically exhibit reduced episodic memory precision, while maintaining relatively preserved retrieval success. However, little is known about whether these age-related differences are influenced by internal biological factors (e.g., chronotype) or external testing conditions (e.g., experiment format, time of day). To address this question, younger and older adults completed an object-location memory task online, either in the morning or evening, and either with or without video-based supervision. Memory performance was assessed using mean absolute error and Bayesian hierarchical mixture modelling, which dissociated memory precision ({kappa}) from the probability of memory-based responding ({theta}). Immediate memory performance was high across age groups, irrespective of time of day. Greater encoding error predicted greater retrieval error, and participants tested in the video condition exhibited lower recall error and higher recognition performance than those tested without supervision. Consistent with prior studies, older adults exhibited reduced memory precision relative to younger adults, whereas retrieval success remained largely intact. However, Bayesian Hierarchical Modelling provided no evidence that time of day, experiment format, or their interactions with age influenced either memory precision or retrieval probability. Older adults reported stronger morning preferences than younger adults, and participants generally selected testing times that aligned with their chronotype. Nevertheless, alignment between chronotype and testing time did not modulate memory performance. The results indicate that age-related differences in episodic memory precision are robust across variations in testing context, including time of day, experiment format, and individual differences in chronotype. More broadly, the results support the feasibility of remote and unsupervised testing for memory precision research and suggest that chronotype and testing time are unlikely to be major sources of variability in immediate object-location memory performance.

Modest positive associations between episodic memory performance and whole hippocampal and hippocampal subfield volumes have been reported in numerous prior studies. A smaller number of studies have reported associations between hippocampal volume and performance on tests of non-mnemonic cognition. The present study examined whether these associations were evident in a lifespan sample of cognitively healthy adults. Of particular interest was whether any identified associations were sensitive to age, and whether associations between subfield volumes and mnemonic and non-mnemonic performance were subfield dependent. We acquired high-resolution T1- and T2-weighted structural images from 163 adults (18-87 years of age). Participants also undertook a comprehensive neuropsychological test battery and an in-scanner test of source memory. Principal components analysis was employed to reduce the neuropsychological test scores to 5 cognitive components. Two components reflected memory performance while the other three reflected different aspects of non-mnemonic cognition. Hippocampal subfields (Cornu Ammonis (CA)1, CA2-3, dentate gyrus (DG) and subiculum) were segmented and measured with the Automated Segmentation of Hippocampus Subfields (ASHS) package. Source memory performance was selectively associated across participants with CA2-3 volume. By contrast, both mnemonic and non-mnemonic component scores derived from the test battery were associated exclusively with the volume of the DG. All associations were age-invariant. The findings indicate that different cognitive domains can be dissociated by virtue of their associations with different hippocampal subfields. Of importance, these associations appear to be life-long and hence are unlikely to reflect individual differences in age-related decline in structural integrity.

Hippocampal sharp-wave ripple (SWR) events occur during post-experience rest and sleep and play a significant role in memory consolidation. Recent ex vivo studies have found orexin-driven neuromodulatory effects on SWR parameters and proposed that they can influence memory consolidation. Additionally, behavioral studies demonstrate contradictory results regarding orexinergic effects on memory acquisition depending on task structure and intervention time. This inconsistency, along with the diffuse spread of orexin receptors (OXR) in the CA1 and CA3 hippocampus, challenges theoretical interpretation of orexinergic effects on memory. To reconcile this problem, we propose a rate-based model linking orexinergic tone-dependent SWR statistics to memory performance. The model combines an encoding module whose gain scales with the global orexinergic tone with a consolidation module driven by OX2R-specific replay dynamics. The model is based on a plasticity rule that considers SWR events as the unit of induction. Therefore, weight change requires sufficient replay content and depolarizing drive. We observed that, depending on the task structure, encoding-dominant learning benefits discrimination as the orexin drive increases. Consolidation-dominant learning shows a non-monotonic relationship with an internal optimum level of orexinergic tone. This interaction highlights that stronger truncation at higher receptor engagement shortens memory replay and reduces the efficacy of the consolidation process. The model predicts that the optimal regime depends on task complexity reflected in sequence length. Together, these results demonstrate how task demands determine whether increased orexinergic drive enhances or impairs effective consolidation and SWR-dependent replay in the hippocampus.

Flexible decision making depends on internal representations that capture the latent structure of a task, allowing prior knowledge to be applied in novel circumstances. Spatial navigation provides a useful model for studying flexible choice behavior, because spatial location is itself a latent variable that must be inferred rather than directly perceived. Here, we trained rats on a navigation task that required them to reach the same goal via two distinct paths from different starting locations, and then return to one of the two starting locations before beginning the next trial. Some rats were trained to rely on distal visual landmarks, allowing task states to be identified from current sensory information, whereas others were trained to rely on path integration, requiring task states to be inferred from self-motion information accumulated over the preceding trajectory. Rats trained to rely on path integration acquired the task similarly to rats trained to rely on distal visual landmarks. However, reliance on path integration enhanced rats' ability to generalize their learning to novel situations, including finding the goal from an untrained starting location and adapting to a relocated goal that reversed learned choice sequences. These findings suggest that reliance on path integration promotes the acquisition and use of mental representations that capture the latent spatial structure of navigational tasks, thereby favoring flexible navigational decisions over rigid retrieval of reinforced responses. More broadly, our findings demonstrate how information available during training can shape representations learned from experience and thereby constrain the flexibility of decision making during inference.

Homeostatic mechanisms adjust synaptic strengths to regulate neuronal activity across wake-sleep cycles. Although sleep supports memory consolidation, limited research has explored how sleep-induced homeostatic changes influence memory outcomes in humans. The EEG-derived aperiodic slope (1/f) could be a candidate measure of homeostatic memory processes through its reflection of neural excitation-inhibition balance. In this study, 27 participants learned object-word pairs, and completed an immediate recognition test before either a nap or equivalent wakeful period. Resting-state EEG was recorded, both before and after learning and the interval, to derive changes in aperiodic slope values. A delayed recognition test then assessed whether changes in the aperiodic slope (i.e., homeostatic activity) across learning and the interval predicted memory accuracy and N400 amplitude, an index of stimulus expectancy and recognition. Our study found evidence to suggest homeostatic renormalisation, for the nap condition only, indicated by a shift towards inhibition across sleep which was inversely related to the slope change across learning. Although the aperiodic slope change across the nap and wake intervals did not predict delayed memory accuracy, a shift towards inhibition during learning was beneficial for memory accuracy, only in the nap condition. Similarly, a shift towards inhibition across learning, followed by a shift towards excitation in the nap condition, predicted reduced N400 amplitudes. This suggests that homeostatic renormalisation across the nap influenced model updating and stimulus expectancy. This study provides evidence for a link between synaptic homeostatic processes and memory consolidation, emphasising the importance of encoding-related aperiodic activity in this relationship.

Background: Transcardial perfusion fixation is widely used to preserve rodent brains for histological and ultrastructural analysis, but protocols can vary in the use of pre-fixation washout, fixative formulation, and osmotic additives. Relatively few studies have directly compared how the chemical composition of the perfusate affects tissue preservation. Methods: Male Sprague-Dawley rats underwent transcardial perfusion using a series of aldehyde-based fixative formulations that varied in fixative composition, use of a phosphate buffered saline washout, and the addition of mannitol or polyethylene glycol 35 kDa (PEG35). Perfusion outcomes were assessed using gross brain morphology, semi-quantitative grading of vascular blood clearance, quantitative detection of residual erythrocytes in whole-slide histological images, and light microscopic measures of cellular visualization and morphology. Perfusate osmolality was measured, and selected specimens were examined by electron microscopy. Results: Substantial vascular blood clearance was frequently achieved with fixative-only perfusion, indicating that a pre-fixation washout was not required to achieve high levels of blood clearance under the conditions tested. Routine light microscopy-based measures of cellular visibility and morphology were broadly similar across treatment groups. Adding mannitol and PEG35 to the fixative solution both led to concentration-dependent gross tissue shrinkage, particularly with PEG35, without correspondingly large or consistent changes on light microscopy. A substantial degree of case-to-case variation in perfusion quality was also observed among animals undergoing nominally similar procedures. Conclusions: Substantial variation in perfusate composition produced relatively modest differences in the light microscopy outcomes examined, despite pronounced effects of osmotic additives on gross brain morphology. There were some cases where perfusion with fixative alone led to near-complete blood vessel clearance, and the use of a preceding phosphate buffered saline washout was not associated with higher vascular clearance scores. The degree of case-to-case variability observed within treatment conditions suggests that procedural factors can play an important role on perfusion quality in addition to perfusate composition.

Intrahippocampal kainate (IHK) is a well-established mouse model of temporal lobe epilepsy, in which focal hippocampal injection of kainic acid induces excitotoxic injury followed by the development of chronic spontaneous seizures. Commercial sources of kainic acid (KA) have increasingly transitioned from naturally derived to synthetic KA, which has introduced a potential source of variability to the implementation of the IHK model. Here, we evaluated injection parameters for synthetic KA, with the goal of identifying conditions that reliably produce spontaneous seizures while minimizing mortality. We found that intrahippocampal injection of 200nL of 5mM synthetic KA resulted in low mortality compared to 50-100nL of 20mM synthetic KA (a dosing range commonly used with naturally derived KA), while robustly inducing TLE-like hippocampal sclerosis and recurrent spontaneous electroclinical seizures. We further demonstrated high inter-animal variability in both seizure frequency and temporal clustering of seizures across animals receiving either injection protocol (200nL of 5mM or 50nL of 20mM). Together, these findings provide a framework for implementing the IHK model with synthetic KA and support its continued use to advance our understanding of the cellular and network mechanisms underlying temporal lobe epilepsy.

Sleep disturbances compromise cognition, and overall physical and mental health; however, animal models of these effects remain limited, and typically impose more extreme disturbances than those experienced by humans. Here, we use behavioural interventions in mice to model two common types of sleep disruption: (1) sleep displacement associated with shiftwork and (2) sleep fragmentation associated with aging and disease. C57BL6/J mice were subjected to either a sleep deprivation protocol (n = 8, females = 4) or a fragmentation protocol (n = 8, females = 4), in which they were completely deprived of sleep or awoken every 2 min respectively, for 12 hours during their typical rest phase (lights-on) across 7 consecutive days. Age-matched control mice (n = 14, females = 7) remained undisturbed in their home cages. Activity during the 12-hour active phase was recorded via infrared motion sensors. After protocol completion, mice were injected with bromodeoxyuridine (BrdU, 200mg/kg) 2 hours prior to brain and blood collection; hippocampal neurogenesis and plasma corticosterone were then assessed. Results show that the sleep deprivation and fragmentation protocols had different, dynamic effects on behaviour; sleep deprivation was associated with an accumulating sleep need, operationalized as progressively reduced locomotor activity across the week, whereas fragmentation produced only an acute reduction of locomotor activity. Cell proliferation rates and corticosterone did not differ from controls. These protocols provide a foundation for future research into the mechanistic links between shiftwork and sleep fragmentation on health and cognition.

The mammillary bodies (MB) are a hypothalamic component of the limbic Papez circuit that plays a critical role in spatial and episodic memory in mammals. Degeneration of the MB occurs in disorders associated with cognitive impairment, including Korsakoff's syndrome and Alzheimer's disease, yet the molecular organization and intrinsic properties of MB neurons remain poorly understood. Recent single-cell RNA sequencing identified multiple transcriptionally distinct neuronal populations within the MB and suggested that they differentially express voltage-gated ion channels that regulate neuronal excitability. Here, we used fluorescence in situ hybridization (FISH) to define the anatomical organization of cluster-enriched molecular markers and determine the spatial distribution of transcripts encoding voltage-gated sodium (NaV), potassium (KV), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels among defined subregions of the mouse MB. We found that marker transcripts occupy characteristic but partially overlapping spatial domains that broadly correspond to classical anatomical subdivisions. In addition, several ion channel transcripts, including Scn1a, Scn2a, Kcnq2, Kcnq3, and Hcn1, exhibited distinct patterns of enrichment across molecularly defined neuronal populations and MB subregions. Multiplex FISH further revealed unexpected co-expression of Scn1a and Scn2a within Pvalb-enriched neuronal populations, while whole-cell recordings demonstrated distinct intrinsic firing properties of neurons in the lateral and medial mammillary nuclei. Together, these findings establish a molecular framework linking neuronal population identity with voltage-gated ion channel expression in the MB and provide a foundation for future studies investigating how cell type-specific differences in intrinsic excitability contribute to memory function and neurological disease.

Sex-steroid hormones influence brain structure across aging, but their relationship to the cerebellum, a region implicated in cognition and vulnerable to age-related decline, remains poorly characterized, particularly longitudinally and across both sexes. We examined whether 17{beta}-estradiol, progesterone, and testosterone relate to cerebellar volume across two timepoints, and whether these relationships differ by sex. In a mixed-sex sample of aging adults (Baseline N = 137; Year 1 N = 93), free salivary hormones and cerebellar lobular volumes were quantified. Linear regression tested cross-sectional, predictive, and change-score hormone-volume associations, and formal hormone-by-sex interactions, in a priori primary and secondary cerebellar lobules of interest. Hormone-cerebellum relationships were consistently sex-differentiated. Estradiol change related to Crus I volume change in opposite directions in males and females, a dissociation extending across bilateral Crus I and Lobule VI, and Right Crus II. In females, greater increases in testosterone were associated with greater decline in Left Crus I and Right Lobule V volumes. In males, testosterone showed no significant associations in primary analyses, however, increases in estradiol were associated with larger volumes. Progesterone showed a male-specific cross-sectional association with Crus II. Several relationships ran opposite to the direction predicted by estradiols established neurotrophic role. Sex-steroid influences on the aging cerebellum are sex-differentiated, regionally specific, and may not be predicted exclusively by cortical or female-focused models. These findings establish the cerebellum as a potential site of sex-specific hormonal influence on brain aging and also further highlight the complexity of the impact of sex-steroid hormones on the aging brain.

The hippocampus is particularly vulnerable to hypoxia, yet freedivers, who repeatedly undergo voluntary breath-hold hypoxia, do not appear to show the memory impairments commonly reported after involuntary hypoxic exposure. We investigated whether freediving training is associated with functional connectivity reorganization at the whole-brain and hippocampal levels, and whether hippocampal connectivity relates to preserved episodic memory performance. Seventeen male recreational freedivers underwent fMRI before and after a 7-month standardized training period, and 20 matched aerobic-trained controls were assessed at baseline. Functional connectivity analyses examined (i) whole-brain ROI-to-ROI connectivity, (ii) seed-to-voxel connectivity from the bilateral hippocampus and selected cortical seeds, and (iii) associations between hippocampal connectivity and episodic memory. Compared with controls, freedivers showed distinct connectivity patterns during apnea and rest. After training, whole-brain analyses revealed reorganization involving salience, frontoparietal, sensorimotor, visual, and cerebellar systems. Hippocampal analyses showed reduced connectivity with sensorimotor and default mode regions, alongside increased connectivity with cerebellar and visual areas, with stronger effects after training. In freedivers, specific post-training hippocampal connectivity was associated with episodic memory performance. These findings suggest that repeated voluntary hypoxia during freediving training is associated with selective functional reorganization of hippocampal and large-scale brain networks. This pattern may reflect adaptive neuroplasticity linked to preserved episodic memory under intermittent hypoxic exposure.

The small GTPase Rem2 is a key signaling molecule involved in synaptic formation, dendritic complexity, spine formation, and regulation of CaMKII-dependent long-term potentiation (LTP). However, it remains unclear how Rem2 explicitly impacts learning and memory. To address this issue, we deleted Rem2 specifically in dorsal CA1 neurons of male and female mice and assessed spatial learning using a spatial object recognition (SOR) task. We found that males outperform females in this behavioral assay and that deleting Rem2 did not impact spatial learning in males. In contrast, Rem2 deletion significantly improved spatial learning in females enabling them to perform as well as males in the SOR task. Using an automated Western blot system to assess all known AMPA- and NMDA-mediated glutamate receptor (AMPAR and NMDAR) subunits in each mouse, we found that the sex-dependent change in SOR we observed was likely due to Rem2 increasing GluN2D expression in the interneurons of female mice only. Furthermore, using S-statistics to compare the overall AMPAR and NMDAR composition among groups, we found that males and females normally have divergent covariance structures but this divergence is eliminated when Rem2 is deleted from CA1 neurons. These results reveal an unexpected role of Rem2 in maintaining sex differences in glutamate receptor composition and spatial learning abilities. To our knowledge, this is the first demonstration of a signaling molecule that confers sexual dimorphism to excitatory synapses. As such, Rem2 may play a critical role in understanding how sex-dependent symptoms of neurodevelopmental and neurodegenerative disorders arise.

Suspension mass cytometry can measure 50 or more markers per cell and is not impacted by cellular autofluorescence, making it an appealing platform for comprehensive phenotyping of single cells in tissue with high innate fluorescence, such as brain. However, this organ is challenging to reduce to a single cell suspension: it is a deeply interconnected tissue rich in extracellular material and contains a wide variety of cell types including neurons, their supporting glia, and hematopoietic cells from peripheral circulation, any or all of which may have competing requirements for survival through the dissociation process. This study compares approaches for producing single-cell preparations from white and gray matter enriched regions of adult mouse brain, testing simple mechanical dissociation, Accutase, and three gentle enzymes plus DNase: papain, collagenase II, and collagenase plus dispase, all with or without Percoll gradient centrifugation to separate intact cells from debris. Live cells were counted by hemocytometer and Trypan blue exclusion to assess yield and compare across enzyme conditions. Mass cytometry was used to assess cellular composition after representative dissociation, debris removal, and viable cryopreservation. Key proteins measured included beta III-tubulin for neurons, glial fibrillary acidic protein (GFAP) for astrocytes, oligodendrocyte transcription factor (OLIG2) for oligodendrocytes, CD31 for endothelial cells, CD24 for ependymal cells, purinergic receptor P2Y12 (P2RY12) for microglia, and CD45 for leukocytes. Mechanical disaggregation paired with enzymatic dissociation by papain, Collagenase/Disapse, or Collagenase II plus DNase produced approximately 400,000 live cells per 100 grams of tissue. Cell yield was not significantly different between conditions and yields were similar between white and grey matter. Addition of Percoll gradient centrifugation substantially reduced the number of viable cells recovered (average decrease of 88%) and resulted in viable cell numbers that were insufficient for robust analysis of less common cell subsets. In addition to neurons, mass cytometry identified six major populations of non-neuronal cells: oligodendrocytes, astrocytes, endothelial cells, ependymal cells, microglia, and leukocytes. The relative abundance of these six populations was generally unchanged by cryopreservation in both grey matter (r = 0.95), and white matter (r = 0.90), though loss of oligodendrocytes did occur in both tissues. Proliferation, as measured by Ki67 positivity, was non-existent; consistent with this, levels of phosphorylated STAT1 (p-STAT1) and p-STAT3 proteins were low in all cell populations and unchanged by cryopreservation. A modest increase in p-S6(S235/236) after cryopreservation was consistently observed only in microglia. Together, these results establish standardized procedures for generating viable single cell suspensions for cytometry that preserve the cellular diversity of the adult murine brain with minimal perturbation of intracellular signaling cascades.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is widely used to train machine learning models for Alzheimer's disease, yet whether it provides consistent ground truth for predictive modeling has not been systematically tested. In this paper, we showed that ADNI contains three interacting sources of bias with direct implications for machine learning: (a) diagnostic label inconsistency, (b) technical measurement drift, and (c) longitudinal survivor bias. A substantial proportion of cases, particularly within intermediate stages, fall outside ADNI's own diagnostic thresholds. MRI field strength and evolving processing pipelines introduce significant technical variability in hippocampal volume, while cohort survivor bias arising from differential retention of participants across phases further distorts longitudinal estimates of disease progression. These findings indicated that ADNI does not provide the stable, internally consistent labels often required in machine learning applications. We proposed a practical framework for diagnostic validation, feature harmonization, and cohort accounting, offering guidance for building more robust and biologically meaningful predictive models from large-scale neuroimaging cohorts.

Hypothalamic supramammillary nucleus (SuM) neurons project to the dentate gyrus and co-release glutamate and GABA, thereby regulating hippocampal information processing. However, how synapses mediating glutamate/GABA co-transmission are established during development remains unclear. Here, we investigated the functional and structural maturation of SuM inputs onto adult-born granule cells (GCs). We found that most newborn GCs received GABAergic responses without detectable glutamatergic responses, whereas a smaller population exhibited glutamate/GABA co-transmission. Newborn GCs with glutamate/GABA co-transmission showed more mature anatomical and physiological properties than GABA-only neurons, with greater dendritic complexity, longer dendritic length, lower input resistance, and stronger medial perforant path inputs. Postsynaptic depolarization failed to induce synapse unsilencing in GABA-only neurons but induced robust long-term potentiation in newborn GCs with glutamatergic transmission, indicating that plasticity at SuM inputs emerges after functional glutamatergic transmission is established. Morphological analysis showed that SuM terminals apposed to newborn GCs contained both VGluT2 and VIAAT, whereas postsynaptic receptor organization remained immature. Moreover, environmental enrichment and chemogenetic activation of SuM neurons increased the proportion of newborn GCs receiving glutamate/GABA co-transmission, suggesting that SuM activity promotes the emergence of glutamatergic transmission. Together, these results suggest that SuM inputs onto newborn GCs undergo sequential maturation from initial GABAergic transmission to glutamate/GABA co-transmission, a process likely supported by SuM activity-dependent postsynaptic maturation.

Hypoxia impairs cognitive function, yet its effects on navigation and intrinsic brain activity remain poorly understood. This study investigated whether a continuous exposure to hypoxia (CH) or an intermittent exposure to hypoxia (IH) differentially influence navigation performance and resting-state electroencephalography (EEG) in healthy young adults. Seventy-two participants completed sham (FiO2 = .209) and hypoxia (FiO2 = .13) sessions during either a one hour of CH or IH intervention. Navigation was assessed using the Spatial Performance Assessment for Cognitive Evaluation (SPACE), while resting-state EEG was recorded before and after the intervention in a subset of participants (n = 40). EEG spectra were parameterised into periodic (alpha and beta power and central frequency) and aperiodic (exponent and offset) components. Aligned rank transform (ART) analyses of variance examined effects of hypoxia and intervention group, while linear regression determined whether reductions in peripheral oxygen saturation (SpO2) predicted changes in navigation or EEG. Hypoxia impaired multiple components of navigation, increasing path integration distance error and egocentric pointing angle error irrespective of intervention group, while mapping accuracy was preferentially impaired following IH and perspective taking performance following CH. Hypoxia also reduced alpha and beta power, beta central frequency, and aperiodic exponent, while aperiodic offset and alpha central frequency remained stable. The reduction in aperiodic exponent was primarily evident following IH, suggesting that the temporal pattern of oxygen delivery may influence specific neurophysiological responses. Contrary to our hypothesis, SpO2 reduction did not predict individual differences in navigation performance or EEG activity. These findings demonstrate that brief, moderate hypoxic exposure can disrupt allocentric and egocentric components of spatial navigation while selectively altering periodic and aperiodic features of intrinsic brain activity.

Objectives: The rising prevalence of financial exploitation among older adults has prompted research on the cognitive mechanisms underlying financial decision making in later life. Prior work has demonstrated a link between cognitive impairment and financial vulnerability. The present study examined the unique contributions of composite measures of memory and executive functioning to scam susceptibility in middle-aged to older adults without dementia. Methods: One hundred and fifty-one participants (age= 68.2 {+/-} 8.0 years, 72.2% female, years of education= 16.4 {+/-} 2.2) completed standard neuropsychological measures from the Uniform Data Set (UDS), Version 3, and the California Verbal Learning Test, Second Edition, and a self-report scam susceptibility measure. Psychometrically robust composite scores, the UDS-M+ and UDS3-EF, were computed to represent memory and executive functioning domains. Linear regression models examined independent associations between UDS-M+ and UDS3-EF performance and scam susceptibility. Nested model comparisons evaluated unique contributions of the UDS-M+ and UDS3-EF when included in a joint model. Results: Lower UDS-M+ (b= -0.25, 95% CI [-0.45, -0.04], p= .018) and lower UDS3-EF (b= -0.33, 95% CI [-0.54, -0.12], p= .002) scores were independently associated with greater scam susceptibility after adjusting for age, sex, years of education, and income. However, only UDS3-EF remained significant in a joint model. Post hoc analyses revealed that only memory was associated with scam susceptibility in middle-aged adults whereas only executive functioning was significant in older adults. Conclusions: These findings highlight the importance of monitoring memory and executive functioning across middle to older adulthood when considering susceptibility to scams.

Deletion of the microtubule-associated protein, tau reduces seizure burden in rodent models of genetic epilepsies and suppresses evoked seizures. In the intrahippocampal kainate (IHK) model of acquired temporal lobe epilepsy (TLE), mice lacking tau expression develop spontaneous seizures, but at a lower rate than controls. Mechanisms by which tau deletion modifies the development of acquired TLE are not well understood, but a modification of the synaptic reorganization that accompanies epileptogenesis may contribute to modified seizure expression. Increased inhibitory synaptic input to dorsal dentate granule cells (DGCs) contralateral to the focal kainate injection results after development of TLE in tau-/- mice, but inhibitory synaptic reorganization distal to the kainate lesion is undefined in this model. We therefore investigated how development of TLE modifies excitability and synaptic transmission in DGCs of the ventral dentate gyrus, distant from the kainate lesion. Our results show that development of TLE increases evoked action potential firing of ventral DGCs (vDGCs) in mice that develop TLE, demonstrating an effect of TLE development on excitability of DGCs distant from the focal injury. After development of TLE, DGCs from tau-/- mice received increased inhibitory synaptic input bilaterally, suggesting that tau expression suppresses inhibitory synaptic reorganization in DGCs. Optogenetic stimulation of interneurons in tau-/- mice revealed increased inhibitory synaptic input to vDGCs and an increase in inhibitory convergence onto vDGCs once epileptogenesis occurred. Therefore, tau deletion modifies spontaneous seizure expression after epileptogenesis in mice, potentially involving increased synaptic inhibition of DGCs throughout the dentate gyrus.

Although dementias primarily affect memory, they also disrupt our closest social relationships, resulting in elevated caregiver burden and worse patient outcomes. However, the mechanistic study of how pathology affects social attachments is limited by the use of laboratory rodents that do not form selective, long-term bonds. Here, in monogamous prairie voles, we expressed dementia-causing tauP301L in the paraventricular hypothalamus of 12- and 18-month-old animals, and separately, from birth through 18-months, across hippocampocortical regions. Hippocampocortical expression of tauP301L did not yield deficits in social or non-social dementia-related phenotypes. In contrast, tauP301L expressed in the hypothalamus yielded sex- and age-dependent social bonding deficits. 18-month males with hypothalamic tau pathology failed to form bonds and displayed blunted sociability, effects that converged across bonding assays. In addition, healthy 18-month males paired with a hypothalamic tau-expressing female also showed reduced partner preference, suggesting that pathology exerts vicarious effects on partners. Social behavior of both healthy females and those expressing tauP301L were unaffected. 18-month tauP301L males also showed elevated oxytocin fluorescence. These findings establish direct and vicarious disruptions to pair bonding induced by hypothalamic tau pathology in male prairie voles, potentially via altered oxytocin signaling.