BACKGROUND:The interthalamic adhesion (IA) is an anatomical bridge connecting the left and right thalamus. While prior studies have explored its prevalence and function in healthy populations, stroke, hydrocephalus, and schizophrenia, none have examined the IA in the context of Alzheimer's disease (AD). This study aims to analyse the prevalence of the IA in the prodromal to clinical AD continuum and evaluate the association with AD cerebrospinal fluid (CSF) biomarkers and thalamic, hippocampal, and ventricular volumes. METHOD:IA prevalence was assessed in 542 MRIs from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including healthy controls (HC), early mild cognitive impairment (EMCI), late MCI (LMCI), and AD patients. Inter-rater reliability was assessed with Cohen's Kappa, and a chi-squared test (χ2) examined rater differences. Binary and multinomial logistic regressions evaluated the effect of CSF biomarkers, volumes, and clinical data on IA prevalence and type. RESULTS:There were no significant differences in IA prevalence or variants across the four groups. The single IA was the most common type, while bilobar and double variants were less frequent. Post-hoc analysis, however, showed that AD CSF biomarker measures showed positive associations with the broad IA subtype in HC and EMCI. CONCLUSION:The study found no overall differences in IA prevalence or its variants related to prodromal or clinical AD. Still, elevated Aβ42, p-Tau levels, and larger thalamic volume were linked to a higher likelihood of a broad IA. These findings suggest that the IA may be involved in prodromal AD pathophysiological processes.

Recognition of a familiar object in a novel location requires retrieval of the former object-place association and encoding of novel information. Such object-in-place (OiP) memory recruits a neural network including the hippocampus (HPC), medial prefrontal cortex (mPFC), and nucleus reuniens of the thalamus (NRe); however, the underlying cellular mechanisms are not understood. Locus ceruleus (LC) noradrenergic neurons signal novelty; thus here we focused on the contribution of LC-forebrain projections and noradrenaline (NA) receptor subtypes to OiP encoding compared with retrieval, using an arena-based OiP task in male rats. The NRe was found to receive a catecholaminergic input from LC, with the strongest innervation directed to rostral NRe. Interestingly optogenetic inactivation of the LC→NRe pathway impaired OiP retrieval but was without effect on encoding, while inactivation of the LC→HPC selectively impaired encoding. Consistent with this double dissociation, pharmacological blockade of NRe α1-adrenoreceptors selectively impaired memory retrieval, while blockade of HPC β-adrenoreceptors impaired encoding. Finally, pharmacological attenuation of noradrenergic signaling in the NRe and HPC through the infusion of the α2-adrenergic receptor agonist UK 14,304 impaired retrieval and encoding, respectively. Surprisingly, antagonism or agonism of adrenoreceptor subtypes in the mPFC had no effect on memory performance. Together these results reveal the importance of NA within the HPC and NRe for OiP, whereby selectivity of function is achieved via spatially distinct LC output projections and NA receptor subtypes consistent with a modular view of NA function. These results are also important in demonstrating the distinct neuronal mechanisms by which encoding and retrieval are achieved.

The retrosplenial cortex (RSC) is a highly interconnected brain region involved in spatial navigation and associative learning. It forms extensive, reciprocal connections with sensory, hippocampal, parahippocampal, prefrontal, and thalamic areas. RSC comprises granular (gRSC) and dysgranular (dRSC) subdivisions with distinct connectivity and functions. Despite its emerging role in behaviour and its implication in memory-related disorders such as Alzheimer's disease, the nature of its synaptic inputs remains poorly understood. Here, we combined viral anatomical tracing, optogenetic stimulation, and patch-clamp electrophysiology to investigate inputs from the anterior cingulate cortex (ACC), dorsal subiculum (dSub), and anterior thalamic nuclei (ATN) to gRSC and dRSC. Strikingly, all recorded RSC pyramidal neurons received ATN input, regardless of subdivision or cortical layer. Activation of ATN inputs evoked significantly larger post-synaptic responses than those from dSub or ACC, though both regions maintained substantial connectivity with RSC. While dSub projections appeared denser in gRSC, synaptic responses were larger in dRSC, albeit with lower input probability. Notably, NMDA receptor-mediated components of RSC excitatory inputs were weaker than expected, potentially explaining the reported inability to induce long-term potentiation in RSC in ex vivo neurophysiology experiments. This is the first study to characterise the synaptic properties of retrosplenial afferents. Our findings highlight the dominant influence of ATN inputs and raise important questions about how RSC's long-range connectivity supports its roles in memory and spatial navigation. ### Competing Interest Statement The authors have declared no competing interest.

Studies of brain-behaviour relationships in hippocampal amnesia largely ignore the presence and explanatory potential of knock-on effects beyond the medial temporal lobes. In a large cohort of patients (n=38) with hippocampal damage due to autoimmune limbic encephalitis, we had reported evidence that extra-hippocampal structural and functional abnormalities in the broader “hippocampal-diencephalic-cingulate network” fully mediated the effects of hippocampal damage on several aspects of episodic memory. However, we had not examined the specific diencephalic nuclei affected or the white matter pathways that would help explain these remote effects. In this study, we used recently developed methods of automated segmentation of diencephalic nuclei, as well as a range of analyses of white matter integrity. As expected, we found atrophy in the anterior thalamic nuclei and in the mammillary bodies, but also in the laterodorsal, pulvinar, and dorsomedial nuclei. The extent of atrophy in some of these nuclei was comparable to, if not larger than that observed for the hippocampal formation, even though none of our patients’ acute clinical scans disclosed thalamic damage. We also present evidence linking these volumes to patients’ episodic memory impairment over and above any correlation with hippocampal/subicular subfield volumes. White matter integrity was strongly compromised in the hippocampal-diencephalic-cingulate network, and the volumetric relationship between the hippocampal formation and the mammillary bodies was at least partly mediated by the integrity of the fornix across patients, consistent with the assumption of Wallerian degeneration following focal medial temporal lobe damage. However, evidence for the specialisation of the “hippocampal-diencephalic-cingulate network” in recollection/recall was mixed, and white matter abnormalities extended to regions well beyond this network. Our findings highlight the need to longitudinally examine diencephalic and white matter integrity in cohorts of hippocampal damage with different aetiologies and update neuroanatomical models of this network. ### Competing Interest Statement The authors have declared no competing interest. Medical Research Council, MR/K010395/1

Alzheimer’s disease (AD) is a neurodegenerative condition characterised by progressive loss of memory and general decline in cognitive function. Although research has traditionally focused on the hippocampus and entorhinal cortex, other regions important for memory and spatial navigation, such as the anterior thalamic nuclei (ATN) and retrosplenial cortex (RSC), are also affected. The RSC is an important brain region for both memory and spatial navigation, and displays dysfunction in humans during prodromal phases of AD. The ATN provide a major input to RSC, with loss of this input to RSC causing a dramatic reduction in the expression of the immediate early gene product c-Fos. The ATN to RSC connection may thus present a new target for therapeutic intervention in AD. Here, we set out to determine whether AD-like pathology perturbed projections from ATN to RSC using the hAPP-J20 amyloidopathy mouse model, using optogenetic activation of thalamic inputs combined with ex vivo patch clamp electrophysiology. We found that RSC displayed an age-dependent decline in basal c-Fos activity, with no additional effect of amyloid pathology on c-Fos expression. At all time points (3, 6 and 9 months) measured, we found no evidence of impairments in the synaptic strength or efficacy of the ATN projections to either granular or dysgranular subdivisions of RSC. We conclude that, in the hAPP-J20 mouse model, this pathway is unaffected by amyloid-β overexpression.

In a changing environment, animals must process spatial signals in a flexible manner. The rat hippocampal formation projects directly upon the retrosplenial cortex, with most inputs arising from the dorsal subiculum and terminating in the granular retrosplenial cortex (area 29). The present study examined whether these same projections are required for spatial working memory and what happens when available spatial cues are altered. Consequently, injections of iDREADDs were made into the dorsal subiculum of rats. In a separate control group, GFP-expressing adeno-associated virus was injected into the dorsal subiculum. Both groups received intracerebral infusions within the retrosplenial cortex of clozapine, which in the iDREADDs rats should selectively disrupt the subiculum to retrosplenial projections. When tested on reinforced T-maze alternation, disruption of the subiculum to retrosplenial projections had no evident effect on the performance of those alternation trials when all spatial-cue types remained present and unchanged. However, the same iDREADDs manipulation impaired performance on all three alternation conditions when there was a conflict or selective removal of spatial cues. These findings reveal how the direct projections from the dorsal subiculum to the retrosplenial cortex support the flexible integration of different spatial cue types, helping the animal to adopt the spatial strategy that best meets current environmental demands.

"The bed nucleus of the stria terminalis (BNST) is a sexually dimorphic basal forebrain region", is a claim prevalent across rodent and human neuroscience research, with particular emphasis on its substantially larger size in males. Despite the pervasiveness of this claim, with potential implications for understanding sex differences in anxiety and substance use disorders, inspection of prior literature reveals a complex and nuanced picture. Direct evidence for larger male BNST size in humans comes solely from a handful of mostly small-scale post-mortem studies, which show either no, moderate, or very large differences, therefore indicating the need for a larger systematic investigation. Addressing this, we developed a novel 3T T1-weighted (T1w) manual segmentation protocol of the BNST, which was applied to T1w structural MRI data in 170 young human adults. Using a Bayesian modelling approach, taking into account existing post-mortem data, and controlling for total brain volume, age, and sibship, we find little evidence for total BNST volume differences between males and females. We recommend that researchers exercise caution when reporting evidence of BNST sexual dimorphism, particularly when translating findings from rodent models in which the BNST may play a different, olfaction-focused, role. ### Competing Interest Statement The authors have declared no competing interest.

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national longitudinal study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls. Cognitive deficits were global and associated with elevated brain injury markers and reduced anterior cingulate cortex volume one year after admission. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Treatment with corticosteroids during the acute phase appeared protective against cognitive deficits. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 is immune-mediated, and should guide the development of therapeutic strategies.

The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies. A national prospective study of patients requiring hospitalization for COVID-19 demonstrates global cognitive deficits at 1 year, associated with elevated brain injury markers and reduced gray matter volume.

Prior univariate functional magnetic resonance imaging (fMRI) studies in humans suggest that the anteromedial subicular complex of the hippocampus is a hub for scene-based cognition. However, it is possible that univariate approaches were not sufficiently sensitive to detect scene-related activity in other subfields that have been implicated in spatial processing (e.g., CA1). Further, as connectivity-based functional gradients in the hippocampus do not respect classical subfield boundary definitions, category selectivity may be distributed across anatomical subfields. Region-of-interest approaches, therefore, may limit our ability to observe category selectivity across discrete subfield boundaries. To address these issues, we applied searchlight multivariate pattern analysis to 7T fMRI data of healthy adults who undertook a simultaneous visual odd-one-out discrimination task for scene and non-scene (including face) visual stimuli, hypothesising that scene classification would be possible in multiple hippocampal regions within, but not constrained to, anteromedial subicular complex and CA1. Indeed, we found that the scene-selective searchlight map overlapped not only with anteromedial subicular complex (distal subiculum, pre/para subiculum), but also inferior CA1, alongside posteromedial (including retrosplenial) and parahippocampal cortices. Probabilistic overlap maps revealed gradients of scene category selectivity, with the strongest overlap located in the medial hippocampus, converging with searchlight findings. This was contrasted with gradients of face category selectivity, which had stronger overlap in more lateral hippocampus, supporting ideas of parallel processing streams for these two categories. Our work helps to map the scene, in contrast to, face processing networks within, and connected to, the human hippocampus.

The dense fiber pathways that connect the insular cortex with frontal cortices are thought to provide these frontal areas with interoceptive information, crucial for their involvement in executive functions. Using anterograde neuroanatomical tracing, we mapped the detailed organization of the projections from the rat insular cortex to its targets in orbitofrontal (OFC) and medial prefrontal (mPFC) cortex. In OFC, main insular projections distribute to lateral and medial parts, avoiding ventral parts. Whereas projections from the primary gustatory cortex densely innervate dorsolateral OFC, likely corresponding to what in primates is known as the secondary gustatory cortex, these projections avoid mPFC. Instead, mPFC is targeted almost exclusively by projections from agranular fields of the insular cortex. Finally, "parietal" domains of the insular cortex project specifically to the dorsolateral OFC, and strongly innervate ventral portions of mPFC, i.e., the dorsal peduncular cortex.

Journal Article Corrected proof Scientific Business Abstracts Get access Keith Siew, Keith Siew University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Vaksha Patel, Vaksha Patel University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Jasminka Zimmermann, Jasminka Zimmermann University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael Vaughan, Michael Vaughan University of Cork, Eire Search for other works by this author on: Oxford Academic PubMed Google Scholar Christopher Cheshire, Christopher Cheshire Crick Institute, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Angela Kubik, Angela Kubik NASA Ames Research Centre, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Rebecca Finch, Rebecca Finch University of Staffordshire, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Zhongwang Li, Zhongwang Li University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Selin Altinok, Selin Altinok University North Carolina, Chapel Hill, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Willian De Silvera, Willian De Silvera University of Staffordshire, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar ... 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The connectivity and interplay between the prefrontal cortex and hippocampus underpin various key cognitive processes, with changes in these interactions being implicated in both neurodevelopmental and neurodegenerative conditions. Understanding the precise cellular connections through which this circuit is organised is, therefore, vital for understanding these same processes. Overturning earlier findings, a recent study described a novel excitatory projection from anterior cingulate area to dorsal hippocampus. We sought to validate this unexpected finding using multiple, complementary methods: anterograde and retrograde anatomical tracing, using anterograde and retrograde adeno-associated viral vectors, monosynaptic rabies tracing, and the Fast Blue classical tracer. Additionally, an extensive data search of the Allen Projection Brain Atlas database was conducted to find the stated projection within any of the deposited anatomical studies as an independent verification of our own results. However, we failed to find any evidence of a direct, monosynaptic glutamatergic projection from mouse anterior cingulate cortex to the hippocampus proper.

To understand the neural basis of episodic memory it is necessary to appreciate the significance of the fornix. This pathway creates a direct link between those temporal lobe and medial diencephalic sites responsible for anterograde amnesia. A collaboration with Andrew Mayes made it possible to recruit and scan 38 patients with colloid cysts in the third ventricle, a condition associated with variable fornix damage. Complete fornix loss was seen in three patients, who suffered chronic long-term memory problems. Volumetric analyses involving all 38 patients then revealed a highly consistent relationship between mammillary body volume and the recall of episodic memory. That relationship was not seen for working memory or tests of recognition memory. Three different methods all supported a dissociation between recollective-based recognition (impaired) and familiarity-based recognition (spared). This dissociation helped to show how the mammillary body-anterior thalamic nuclei axis, as well as the hippocampus, is vital for episodic memory yet is not required for familiarity-based recognition. These findings set the scene for a reformulation of temporal lobe and diencephalic amnesia. In this revised model, these two regions converge on overlapping cortical areas, including retrosplenial cortex. The united actions of the hippocampal formation and the anterior thalamic nuclei on these cortical areas enable episodic memory encoding and consolidation, impacting on subsequent recall.

As the functional properties of a cortical area partly reflect its thalamic inputs, the present study compared collateral projections arising from various rostral thalamic nuclei that terminate across prefrontal (including anterior cingulate) and retrosplenial areas in the rat brain. Two retrograde tracers, fast blue and cholera toxin B, were injected in pairs to different combinations of cortical areas. The research focused on the individual anterior thalamic nuclei, including the interanteromedial nucleus, nucleus reuniens and the laterodorsal nucleus. Of the principal anterior thalamic nuclei, only the anteromedial nucleus contained neurons reaching both the anterior cingulate cortex and adjacent cortical areas (prefrontal or retrosplenial), though the numbers were modest. For these same cortical pairings (medial prefrontal/anterior cingulate and anterior cingulate/retrosplenial), the interanteromedial nucleus and nucleus reuniens contained slightly higher proportions of bifurcating neurons (up to 11% of labelled cells). A contrasting picture was seen for collaterals reaching different areas within retrosplenial cortex. Here, the anterodorsal nucleus, typically provided the greatest proportion of bifurcating neurons (up to 15% of labelled cells). While individual neurons that terminate in different retrosplenial areas were also found in the other thalamic nuclei, they were infrequent. Consequently, these thalamo-cortical projections predominantly arise from separate populations of neurons with discrete cortical termination zones, consistent with the transmission of segregated information and influence. Overall, two contrasting medial-lateral patterns of collateral projections emerged, with more midline nuclei, for example, nucleus reuniens and the interoanteromedial nucleus innervating prefrontal areas, while more dorsal and lateral anterior thalamic collaterals innervated retrosplenial cortex.

Standard models of episodic memory focus on hippocampal–parahippocampal interactions, with the neocortex supplying sensory information and providing a final repository of mnemonic representations. However, recent advances have shown that other regions make distinct and equally critical contributions to memory. In particular, there is growing evidence that the anterior thalamic nuclei have a number of key cognitive functions that support episodic memory. In this article, we describe these findings and argue for a core, tripartite memory system, comprising a ‘temporal lobe’ stream (centred on the hippocampus) and a ‘medial diencephalic’ stream (centred on the anterior thalamic nuclei) that together act on shared cortical areas. We demonstrate how these distributed brain regions form complementary and necessary partnerships in episodic memory formation. Accumulating evidence indicates that the anterior thalamic nuclei make important contributions to cognition. Aggleton and O’Mara review these findings and propose that the anterior thalamic nuclei, hippocampus and cortex act together to support episodic memory function.

Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural pathways mediating hippocampal regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. A clear characterisation of the connections linking the subiculum and BNST in humans and non-human primates is lacking. To address this, we first delineated the projections from the subiculum to the BNST using anterograde tracers injected into macaque monkeys, revealing evidence for a monosynaptic subiculum-BNST projection involving the fornix. Second, we used in vivo diffusion MRI tractography in macaques and humans to demonstrate substantial subiculum complex connectivity to the BNST in both species. This connection was primarily carried by the fornix, with additional connectivity via the amygdala, consistent with rodent anatomy. Third, utilising the twin-based nature of our human sample, we found that microstructural properties of these tracts were moderately heritable (h2 ∼ 0.5). In a final analysis, we found no evidence of any significant association between subiculum complex-BNST tract microstructure and indices of perceived stress/dispositional negativity and alcohol use, derived from principal component analysis decomposition of self-report data. Our findings address a key translational gap in our knowledge of the neurocircuitry regulating stress.

Characterizing age- and risk-related hippocampal vulnerabilities may inform about the neural underpinnings of cognitive decline. We studied the impact of three risk-factors, Apolipoprotein (APOE)-ε4, a family history of dementia, and central obesity, on the CA1, CA2/3, dentate gyrus and subiculum of 158 cognitively healthy adults (38-71 years). Subfields were labelled with the Automatic Segmentation of Hippocampal Subfields and FreeSurfer (version 6) protocols. Volumetric and microstructural measurements from quantitative magnetization transfer and Neurite Orientation Density and Dispersion Imaging were extracted for each subfield and reduced to three principal components capturing apparent myelin/neurite packing, size/complexity, and metabolism. Aging was associated with an inverse U-shaped curve on myelin/neurite packing and affected all subfields. Obesity led to reductions in myelin/neurite packing and size/complexity regardless of APOE and family history of dementia status. However, amongst individuals with a healthy Waist-Hip-Ratio, APOE ε4 carriers showed lower size/complexity than non-carriers. Segmentation protocol type did not affect this risk pattern. These findings reveal interactive effects between APOE and central obesity on the hippocampal formation of cognitively healthy adults.

After more than 80 years, Papez serial circuit remains a hugely influential concept, initially for emotion, but in more recent decades, for memory. Here, we show how this circuit is anatomically and mechanistically naïve as well as outdated. We argue that a new conceptualisation is necessitated by recent anatomical and functional findings that emphasize the more equal, working partnerships between the anterior thalamic nuclei and the hippocampal formation, along with their neocortical interactions in supporting, episodic memory. Furthermore, despite the importance of the anterior thalamic for mnemonic processing, there is growing evidence that these nuclei support multiple aspects of cognition, only some of which are directly associated with hippocampal function. By viewing the anterior thalamic nuclei as a multifunctional hub, a clearer picture emerges of extra-hippocampal regions supporting memory. The reformulation presented here underlines the need to retire Papez serially processing circuit.

Both nucleus reuniens and the anterior thalamic nuclei are densely interconnected with medial cortical and hippocampal areas, connections that reflect their respective contributions to learning and memory. To better appreciate their comparative roles, pairs of different retrograde tracers were placed in these two thalamic sites in adult rats. Both thalamic sites receive modest cortical inputs from layer V that contrasted with much denser projections from layer VI. Despite frequent overlap in layer VI, ventral prefrontal and anterior cingulate inputs to nucleus reuniens were concentrated in the deepest sublayer (VIb). Meanwhile, inputs to the anterior thalamic nuclei originated more evenly from both sublayers VIa and VIb, with the result that they were often located more superficially than the projections to nucleus reuniens. Again, while the many hippocampal (subiculum) neurons projecting to nucleus reuniens and the anterior thalamic nuclei were partially intermingled within the deep cellular parts of the subiculum, cells projecting to nucleus reuniens consistently tended to lie even deeper (i.e., immediately adjacent to the alveus). Variable numbers of double-labeled cells were present in those cortical and subicular portions where the two cell populations intermingled, though they remained in a minority. Our data also show how projections to these two thalamic sites are organized in opposing dorsal/ventral and rostral/caudal gradients across both the cortex and hippocampal formation. While the anterior thalamic nuclei are preferentially innervated by dorsal cortical sites, more ventral frontal sites preferentially reach nucleus reuniens. These anatomic differences may underpin the complementary cognitive functions of these two thalamic areas.