Search

Data deposited for the published manuscript: Xu Z, Wu W, Winter SS, Mehlman ML, Butler WN, Simmons C, Harvey RE, Berkowitz LE, Chen Y, Taube JS, Wilber AA, Clark BJ. (2019). A comparison of neural decoding methods and population coding across thalamo-cortical head direction cells. Frontiers in Neural Circuits. 13, 75. doi: 10.3389/fncir.2019.00075 Abstract: Head direction (HD) cells, which fire action potentials whenever an animal points its head in a particular direction, are thought to subserve the animal’s sense of spatial orientation. HD cells are found prominently in several thalamo-cortical regions including anterior thalamic nuclei, postsubiculum, medial entorhinal cortex, parasubiculum, and the parietal cortex. While a number of methods in neural decoding have been developed to assess the dynamics of spatial signals within thalamo-cortical regions, studies conducting a quantitative comparison of machine learning and statistical model-based decoding methods on HD cell activity are currently lacking. Here, we compare statistical model-based and machine learning approaches by assessing decoding accuracy and evaluate variables that contribute to population coding across thalamo-cortical HD cells.

The hippocampus is necessary for binding and reconstituting information in relational memory. These essential memory functions are supported by the distinct cytoarchitecture of the hippocampal subfields. Magnetic resonance elastography is an emerging tool that provides sensitive estimates of microstructure vis-à-vis tissue mechanical properties. Here, we report the first in vivo study of human hippocampal subfield viscoelastic stiffness and damping ratio. Stiffness describes resistance of a viscoelastic tissue to a stress and is thought to reflect the relative composition of tissue at the microscale; damping ratio describes relative viscous-to-elastic behavior and is thought to generally reflect microstructural organization. Measures from the subiculum (combined with presubiculum and parasubiculum), cornu ammonis (CA) 1–2, and CA3-dentate gyrus (CA3-DG) were collected in a sample of healthy, cognitively normal men (n = 20, age = 18–33 years). In line with known cytoarchitecture, the subiculum demonstrated the lowest damping ratio, followed by CA3-DG and then combined CA1–CA2. Moreover, damping ratio of the CA3-DG—potentially reflective of number of cells and their connections—predicted relational memory accuracy and alone replicated most of the variance in performance that was explained by the whole hippocampus. Stiffness did not differentiate the hippocampal subfields and was unrelated to task performance in this sample. Viscoelasticity measured with magnetic resonance elastography appears to be sensitive to microstructural properties relevant to specific memory function, even in healthy younger adults, and is a promising tool for future studies of hippocampal structure in aging and related diseases.

The organization of projections from the macaque monkey hippocampus, subiculum, presubiculum, and parasubiculum to the entorhinal cortex was analyzed using anterograde and retrograde tracing techniques. Projections exclusively originate in the CA1 field of the hippocampus and in the subiculum, presubiculum, and parasubiculum. The CA1 and subicular projections terminate most densely in Layers V and VI of the entorhinal cortex, with sparser innervation of the deep portion of Layers III and II. Entorhinal projections from CA1 and the subiculum are topographically organized such that a rostrocaudal axis of origin is related to a medial-to-lateral axis of termination. A proximodistal axis of origin in CA1 and distoproximal axis in subiculum are related to a rostrocaudal axis of termination in the entorhinal cortex. The presubiculum sends a dense, bilateral projection to caudal parts of the entorhinal cortex. This projection terminates most densely in Layer III with sparser termination in Layers I, II, and V. The same parts of entorhinal cortex receive a dense projection from the parasubiculum. This projection terminates in Layers III and II. Both presubicular and parasubicular projections demonstrate the same longitudinal topographic organization as the projections from CA1 and the subiculum. These studies demonstrate that: (a) hippocampal and subicular inputs to the entorhinal cortex in the monkey are organized similar to those described in nonprimate species; (b) the topographic organization of the projections from the hippocampus and subicular areas matches that of the reciprocal projections from the entorhinal cortex to the hippocampus and the subicular areas.

The present study aims to give detailed histomorphological features of the hippocampus of adult male New Zealand rabbits. Both histological and histochemical specimens were prepared to be examined microscopically by using a light microscope. The hippocampus appeared as C-shaped hippocampal proper, dentate gyrus, and subiculum. The hippocampal proper subdivided along its length according to the density and size of its major constituent pyramidal cells into four distinct regions named Cornu Ammonis (CA1, CA2, CA3, and CA4). With the histochemical preparations, each of these regions consisted of five layers, stratum alveolus, stratum oriens, stratum pyramidale, stratum radiatum, and stratum lacunosum-moleculare. The stratum pyramidale constituted the middle dark zone and contained the principal excitatory neurons and a few interneurons. Histochemically, the pyramidal neurons along all regions of the CA reacted positively to Grimelius silver impregnation, lead hematoxylin, Gomori's aldehyde fuchsin, aldehyde thionine, Gomori's chrome alum hematoxylin, and performic acid alcian blue stains. Immunohistochemically, the pyramidal neurons reacted positively to anti-NSE antibodies. The dentate gyrus was formed of three distinct layers. The subiculum was formed of proper subiculum, presubiculum, and parasubiculum.

An essential role of the hippocampal region is to integrate information to compute and update representations. How this transpires is highly debated. Many theories hinge on the integration of self-motion signals and the existence of continuous attractor networks (CAN). CAN models hypothesise that neurons coding for navigational correlates – such as position and direction – receive inputs from cells conjunctively coding for position, direction and self-motion. As yet, such conjunctive coding had not been found in the hippocampal region. Here, we report neurons coding for angular and linear velocity, distributed across the medial entorhinal cortex, the presubiculum and the parasubiculum. These self-motion neurons often conjunctively encoded position and/or direction, yet lacked a structured organisation, calling for the revision of current CAN models. These results offer insights as to how linear/angular speed – derivative in time of position/direction – may allow the updating of spatial representations, possibly uncovering a generalised algorithm to update any representation.

SummaryThe medial entorhinal cortex (MEC) creates a map of local space, based on the firing patterns of grid, head direction (HD), border, and object-vector (OV) cells. How these cell types are organized anatomically is debated. In-depth analysis of this question requires collection of precise anatomical and activity data across large populations of neurons during unrestrained behavior, which neither electrophysiological nor previous imaging methods fully afford. Here we examined the topographic arrangement of spatially modulated neurons in MEC and adjacent parasubiculum using miniaturized, portable two-photon microscopes, which allow mice to roam freely in open fields. Grid cells exhibited low levels of co-occurrence with OV cells and clustered anatomically, while border, HD and OV cells tended to intermingle. These data suggest that grid-cell networks might be largely distinct from those of border, HD and OV cells and that grid cells exhibit strong coupling among themselves but weaker links to other cell types.Highlights- Grid and object vector cells show low levels of regional co-occurrence- Grid cells exhibit the strongest tendency to cluster among all spatial cell types- Grid cells stay separate from border, head direction and object vector cells- The territories of grid, head direction and border cells remain stable over weeks

Oscillations are a hallmark of brain activity and can be generated by local synchronisation mechanisms. They have been implicated in the communication between brain areas. An important type of oscillations are �� oscillations (4-12 Hz), which are associated with different behaviours, such as movements and navigation, but they also play a crucial role in memory formation and retrieval. One of the major �� rhythm generators in the brain is the medial septum (MS), which with its different types of projecting neurons, innervates many cortical areas and synchronises their activity. I investigated two major projection types of the MS: GABAergic (��-aminobutyric acid ��� GABA) and cholinergic (acetylcholine ��� ACh) projections. Both projections are known to target the medial entorhinal cortex (MEC) and hippocampus. Parvalbumin positive (PV+) projections of the MS, which are GABAergic, are known to synchronise cortical networks via disinhibition often by inhibiting interneurons. In contrast, cholinergic projections of the MS project to a wide range of cell types in the MEC and hippocampus and can have substantially different effects on the target cell (e.g. activation or inhibition). Thus, their function on a network can range from increasing activity through depolarising excitatory cells, to more inhibition of the network by activating interneurons, or even modulating synaptic integration. Previous studies have focussed on identifying projections to the hippocampus and the MEC but did not consider the parasubiculum (PaS), a major input of the MEC. In this study, we electrophysiologically characterised cells in the PaS and demonstrated layer I interneurons to be distinctly different from putative layer II interneurons. The PaS, with its strong �� rhythmic firing cells, was shown to have the highest density of MS PV+ fibres in the parahippocampal formation, suggesting that it is an important target of MS projections and yet MS inputs to the PaS are unknown. Using channelrhodopsin (ChR2), a light sensitive ion channel, expressed in the MS of PV-Cre and ChAT-Cre (choline acetyltransferase) mice in-vivo, I identified GABAergic and cholinergic MS connections to the PaS in-vitro and demonstrated cell type specific projection patterns. I found that PV+ MS projections mainly inhibit interneurons in the PaS, including layer I interneurons, representing a novel cortical target of PV+ MS cells. On the other hand, cholinergic projections depolarise layer I interneurons and have multiple effects on deeper cells of the PaS, leading to a depolarisation or hyperpolarisation. To investigate a potential role of GABAergic projections in �� generation, I recorded local field potentials (LFP) in awake head-fixed mice and entrained oscillations in the PaS by stimulating with light in the MS. In contrast, local stimulation of fibres in the PaS could not entrain oscillation, suggesting that increased activity in the PaS might be required for MS PV+ cells to entrain ��. Taken together, stimulation of PV+ cells in the MS is sufficient to drive oscillations in the PaS, likely via disinhibition in line with other areas as the MEC and hippocampus. However, novel targets in layer I could be involved via cholinergic activation and GABAergic entrainment. Whether cholinergic activation by itself can entrain �� remains to be further investigated., Oszillationen sind ein Kennzeichen von Gehirnaktivit��t und k��nnen durch lokale Synchronisationsmechanismen generiert werden. Sie spielen eine wichtige Rolle bei der Kommunikation zwischen Gehirnarealen. Ein wichtiger Typ von Oszillationen sind �� Oszillationen (4 ��� 12 Hz), welche mit verschiedenen Verhalten wie Bewegung und Navigation assoziiert sind und eine wichtige Rolle in der Ged��chtnisbildung und -abrufung spielen. Einer der wichtigen �� Generatoren im Gehirn ist das Mediale Septum (MS), welches mit seinen verschiedenen projizierenden Neuronen viele kortikale Regionen innerviert. Ich habe zwei Typen von Projektionen des MS untersucht: GABAerge (��-Aminobutters��ure ��� GABA) und cholinerge (Acetylcholin ��� ACh) Projektionen. Beide Typen projizieren zum Medialen Entohinalen Kortex (MEC) und zum Hippocampus. Parvalbumin positive (PV+) Projektionen des MS k��nnen kortikale Netzwerke via Disinhibition, durch inhibieren von Interneuronen, synchronisieren. Im Gegensatz dazu projizieren cholinerge Projektionen des MS zu verschiedensten Zelltypen des MEC und des Hippocampus und k��nnen unterschiedliche weitreichende Effekte auf Zellen haben (z.B. Aktivierung und Inhibierung). Folglich k��nnen die Konsequenzen von Aktivierung des Netzwerkes via Depolarisation von exzitatorischen Zellen, ��ber Inhibierung des Netzwerkes via Aktivierung von Interneuronen bis hin zur Modulation von synaptischer Integration reichen. In der Vergangenheit haben Studien sich auf die Identifizierung von Projektionen zum Hippocampus und MECs fokussiert, jedoch nicht zum Parasubiculum (PaS), eines der bedeutendsten Eing��nge des MEC. In dieser Studie haben wir elektrophysiologisch Zellen im PaS charakterisiert und konnten herausstellen, dass Schicht I Zellen sich von anderen vermeintlichen Interneuronen in Schicht II unterscheiden. Das PaS, mit seinen im �� Rhythmus feuernden Zellen, hat die h��chste Dichte von MS PV+ Fasern im parahippocampalen Netzwerk, was es als besonderes Ziel f��r MS Projektionen herausstellt. Dennoch sind Projektionen vom MS zum PaS nicht untersucht worden. Mit Hilfe von Channelrhodopsin (ChR2), einem lichtsensitivem Ionenkanal, welcher im MS von PV-Cre und ChAT-Cre M��usen exprimiert wurde, konnte ich GABAerge und cholinerge MS Verbindungen zum PaS in-vitro detektieren und Zelltyp-speziefische Projektionen identifizieren. Ich konnte herausstellen, dass PV+ MS Projektionen haupts��chlich Interneurone im PaS inhibieren. Insbesondere Schicht I Interneurone stellen ein neues kortikales Ziel von PV+ MS Zellen dar. Im Gegensatz dazu werden Schicht I Interneurone des PaS durch cholinerge MS Projektionen depolarisiert wohingegen Zellen in tieferen Schichten depolarisiert oder hyperpolarisiert werden k��nnen. Um zu zeigen, dass man mit GABAergen Projektionen �� generieren kann, nahm ich das lokale Feldpotential (LFP) in Kopffixierten M��usen auf und fand, dass man Oszillationen mit MS-Stimulation gleichschalten kann, jedoch eine Stimulation der Fasern im PaS nicht ausreichend ist. Das weist darauf hin, dass eine erh��hte PaS-Aktivit��t notwendig ist, um �� Oszillationen im PaS zu generieren. Zusammenfassend zeigt sich, dass eine Stimulation der PV+ Zellen im MS ausreichend ist, um im PaS Oszillationen zu generieren. Disinhibierung im PaS ist, ��hnlich wie auch im MEC und Hippocampus, ein wahrscheinlicher Mechanismus. Weiterhin k��nnten jedoch neue Ziele von cholinergen und GABAergen Fasern in Schicht I bei der �� Generierung involviert sein. Ob �� Oszillationen durch cholinerge Projektionen gleichgeschaltet werden kann muss jedoch noch durch weitere Studien gezeigt werden.

While age‐related volumetric changes in human hippocampal subfields have been reported, little is known about patterns of subfield functional connectivity (FC) in the context of healthy ageing. Here we investigated age‐related changes in patterns of FC down the anterior–posterior axis of each subfield. Using high resolution structural MRI we delineated the dentate gyrus (DG), CA fields (including separating DG from CA3), the subiculum, pre/parasubiculum, and the uncus in healthy young and older adults. We then used high resolution resting state functional MRI to measure FC in each group and to directly compare them. We first examined the FC of each subfield in its entirety, in terms of FC with other subfields and with neighboring cortical regions, namely, entorhinal, perirhinal, posterior parahippocampal, and retrosplenial cortices. Next, we analyzed subfield to subfield FC within different portions along the hippocampal anterior–posterior axis, and FC of each subfield portion with the neighboring cortical regions of interest. In general, the FC of the older adults was similar to that observed in the younger adults. We found that, as in the young group, the older group displayed intrinsic FC between the subfields that aligned with the tri‐synaptic circuit but also extended beyond it, and that FC between the subfields and neighboring cortical areas differed markedly along the anterior–posterior axis of each subfield. We observed only one significant difference between the young and older groups. Compared to the young group, the older participants had significantly reduced FC between the anterior CA1‐subiculum transition region and the transentorhinal cortex, two brain regions known to be disproportionately affected during the early stages of age‐related tau accumulation. Overall, these results contribute to ongoing efforts to characterize human hippocampal subfield connectivity, with implications for understanding hippocampal function and its modulation in the ageing brain.

Brain circuits are comprised of distinct interconnected neurons that are assembled by synaptic recognition molecules presented by defined pre- and post-synaptic neurons. This cell-cell recognition process is mediated by varying cellular adhesion molecules, including the latrophilin family of adhesion G-protein-coupled receptors. Focusing on parahippocampal circuitry, we find that latrophilin-2 (Lphn2; gene symbol ADGRL2) is specifically enriched in interconnected subregions of the medial entorhinal cortex (MEC), presubiculum (PrS), and parasubiculum (PaS). Retrograde viral tracing from the Lphn2-enriched region of the MEC reveals unique topographical patterning of inputs arising from the PrS and PaS that mirrors Lphn2 expression. Using a Lphn2 conditional knockout mouse model, we find that deletion of MEC Lphn2 expression selectively impairs retrograde viral labeling of inputs arising from the ipsilateral PrS. Combined with analysis of Lphn2 expression within the MEC, this study reveals Lphn2 to be selectively expressed by defined cell types and essential for MEC-PrS circuit connectivity.

Convulsive status epilepticus (SE) in immature life is often associated with lasting neurobiological changes. We provoked SE by pentylenetetrazole in postnatal day 20 rat pups and examined communication modalities between the temporal hippocampus and medial entorhinal cortex (mEC) in vitro. After a minimum of 40 days post-SE, we prepared combined temporal hippocampal - medial entorhinal cortex (mEC) slices from conditioned (SE) and naïve (N) adult rats and recorded 4-aminopyridine-induced spontaneous epileptiform interictal-like discharges (IED) simultaneously from CA3 and mEC layer V-VI. We analyzed IED frequency and high frequency oscillations (HFOs) in intact slices and after surgical separation of hippocampus from mEC, by two successive incisions (Schaffer collateral cut, Parasubiculum cut). In all slices, IED frequency was higher in CA3 vs mEC and Raster plots indicated no temporal coincidence between them either in intact or in CA1-cut slices. IED frequency was significantly higher in SE mEC, but similar in SE and N CA3, independently of connectivity state. Ripples (R) and Fast Ripples (FR) coincided with IEDs and their power differed between SE and N intact slices, both in CA3 and mEC. CA3 FR/R ratios were higher in the absence of mEC. Moreover, SE (vs N) slices showed significantly higher FR/R ratios independently of the presence of mEC. Taken together, these findings suggest lasting effects of immature SE in network dynamics governing hippocampal-entorhinal communication which may impact adult cognitive, behavioral and/or seizure threshold sequalae.HIGHLIGHTSEarly-life Status Epilepticus (SE) impacts on the adult hippocampal – entorhinal communication in the in vitro 4-AP modelPost-SE CA3 output decreases in HFO power with no change in interictal discharge frequencyPost-SE mEC output increases both in HFO power and interictal discharge frequencyInterictal HFO dynamics in CA3-mEC change upon the connectivity state of the two areas and priorhistory of early-life SE

BackgroundCognitive frailty is a particular state of cognitive vulnerability toward dementia with neuropathological hallmarks. The hippocampus is a complex, heterogeneous structure closely relates to the cognitive impairment in elderly which is composed of 12 subregions. Atrophy of these subregions has been implicated in a variety of neurodegenerative diseases. The aim of this study was to explore the changes in hippocampal subregions in older adults with cognitive frailty and the relationship between subregions and cognitive impairment as well as physical frailty.MethodsTwenty-six older adults with cognitive frailty and 26 matched healthy controls were included in this study. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA) scale (Fuzhou version) and Wechsler Memory Scale-Revised Chinese version (WMS-RC), while physical frailty was tested with the Chinese version of the Edmonton Frailty Scale (EFS) and grip strength. The volume of the hippocampal subregions was measured with structural brain magnetic resonance imaging. Partial correlation analysis was carried out between the volumes of hippocampal subregions and MoCA scores, Wechsler’s Memory Quotient and physical frailty indexes.ResultsA significant volume decrease was found in six hippocampal subregions, including the bilateral presubiculum, the left parasubiculum, molecular layer of the hippocampus proper (molecular layer of the HP), and hippocampal amygdala transition area (HATA), and the right cornu ammonis subfield 1 (CA1) area, in older adults with cognitive frailty, while the proportion of brain parenchyma and total number of white matter fibers were lower than those in the healthy controls. Positive correlations were found between Wechsler’s Memory Quotient and the size of the left molecular layer of the HP and HATA and the right presubiculum. The sizes of the left presubiculum, molecular of the layer HP, and HATA and right CA1 and presubiculum were found to be positively correlated with MoCA score. The sizes of the left parasubiculum, molecular layer of the HP and HATA were found to be negatively correlated with the physical frailty index.ConclusionSignificant volume decrease occurs in hippocampal subregions of older adults with cognitive frailty, and these changes are correlated with cognitive impairment and physical frailty. Therefore, the atrophy of hippocampal subregions could participate in the pathological progression of cognitive frailty.

The parasubiculum (PaS) is located within the parahippocampal region, where it is thought to be involved in the processing of spatial navigational information. It contains a number of functionally specialized neuron types including grid cells, head direction cells, and border cells; and provides input into layer 2 of the medial entorhinal cortex where grid cells are abundantly located. The local circuitry within the PaS remains so far undefined but may provide clues as to the emergence of spatially tuned firing properties of neurons in this region. We used simultaneous patch-clamp recordings to determine the connectivity rates between the 3 major groups of neurons found in the PaS. We find high rates of interconnectivity between the pyramidal class and interneurons, as well as features of pyramid-to-pyramid interactions indicative of a nonrandom network. The microcircuit that we uncover shares both similarities and divergences to those from other parahippocampal regions also involved in spatial navigation.

The parasubiculum is located within the parahippocampal region, where it is thought to be involved in the processing of spatial navigational information. It contains a number of functionally specialised neuron types including grid cells, head direction cells and border cells, and provides input into layer 2 of the medial entorhinal cortex where grid cells are abundantly located. The local circuitry within the parasubiculum remains so far undefined but may provide clues as to the emergence of spatially tuned firing properties of neurons in this region. We used simultaneous patch-clamp recordings to determine the connectivity rates between the three major groups of neurons found in the parasubiculum. We find high rates of interconnectivity between the pyramidal class and interneurons, as well as features of pyramid to pyramid interactions indicative of a non-random network. The microcircuit that we uncover shares both similarities and divergences to those from other parahippocampal regions also involved in spatial navigation.

The hippocampus is known to be comprised of several subfields, but the developmental trajectories of these subfields are under debate. In this study, we analyzed magnetic resonance imaging (MRI) data from a cross-sectional sample (198 healthy Chinese) using an automated segmentation tool to delineate the development of the hippocampal subregions from 6 to 26 years of age. We also examined whether gender and hemispheric differences influence the development of these subregions. For the whole hippocampus, the trajectory of development was observed to be an inverse-u. A significant increase in volume with age was found for most of the subregions, except for the L/R-parasubiculum, L/R-fimbria, and L-HATA. Gender-related differences were also found in the development of most subregions, especially for the hippocampal tail, CA1, molecular layer HP, GC-DG, CA3, and CA4, which showed a consistent increase in females and an early increase followed by a decrease in males. A comparison of the average volumes showed that the right whole hippocampus was significantly larger, along with the R-presubiculum, R-hippocampal-fissure, L/R-CA1, and L/R-molecular layer HP in males in comparison to females. Additionally, the average volume of the right hemisphere was shown to be significantly larger for the hippocampal tail, CA1, molecular layer HP, GC-DG, CA3, and CA4. However, for the presubiculum, parasubiculum, and fimbria, the left side was shown to be larger. In conclusion, the hippocampal subregions appear to develop in various ways from childhood to adulthood, with both gender and hemispheric differences affecting their development.

Structural integrity of the human hippocampus is widely acknowledged to be necessary for the successful encoding and retrieval of autobiographical memories. However, evidence for an association between hippocampal volume and the ability to recall such memories in healthy individuals is mixed. Here we examined this issue further by combining two approaches. First, we focused on the anatomically distinct subregions of the hippocampus where more nuanced associations may be expressed compared to considering the whole hippocampal volume. A manual segmentation protocol of hippocampal subregions allowed us to separately calculate the volumes of the dentate gyrus/CA4, CA3/2, CA1, subiculum, pre/parasubiculum and uncus. Second, a critical feature of autobiographical memories is that they can span long time periods, and so we sought to consider how memory details persist over time by conducting a longitudinal study whereby participants had to recall the same autobiographical memories on two visits spaced 8 months apart. Overall, we found that there was no difference in the total number of internal (episodic) details produced at Visits 1 and 2. However, further probing of detail subcategories revealed that specifically the amount of subjective thoughts and emotions included during recall had declined significantly by the second visit. We also observed a strong correlation between left pre/parasubiculum volume and the amount of autobiographical memory internal details produced over time. This positive relationship was evident for particular facets of the memories, with remembered events, perceptual observations and thoughts and emotions benefitting from greater volume of the left pre/parasubiculum. These preliminary findings expand upon existing functional neuroimaging evidence by highlighting a potential link between left pre/parasubiculum volume and autobiographical memory. A larger pre/parasubiculum appears not only to protect against memory decay, but may possibly enhance memory persistence, inviting further scrutiny of the role of this brain region in remote autobiographical memory retrieval.

The hippocampus is a brain region critical for learning and memory, and is also implicated in several neuropsychiatric disorders that show sex differences in prevalence, symptom expression, and mean age of onset. On average, males have larger hippocampal volumes than females, but findings are inconclusive after adjusting for overall brain size. Although the hippocampus is a heterogenous structure, few studies have focused on sex differences in the hippocampal subfields – with little consensus on whether there are regionally specific sex differences in the hippocampus after adjusting for brain size, or whether it is important to adjust for total hippocampal volume (HPV). Here, using two young adult cohorts from the Queensland Twin IMaging study (QTIM; N ​= ​727) and the Human Connectome Project (HCP; N ​= ​960), we examined differences between males and females in the volumes of 12 hippocampal subfields, extracted using FreeSurfer 6.0. After adjusting the subfield volumes for either HPV or brain size (brain segmentation volume (BSV)) using four controlling methods (allometric, covariate, residual and matching), we estimated the percentage difference of the sex effect (males versus females) and Cohen's d using hierarchical general linear models. Males had larger volumes compared to females in the parasubiculum (up to 6.04%; Cohen's d ​= ​0.46) and fimbria (up to 8.75%; d ​= ​0.54) after adjusting for HPV. These sex differences were robust across the two cohorts and multiple controlling methods, though within cohort effect sizes were larger for the matched approach, due to the smaller sub-sample. Additional sex effects were identified in the HCP cohort and combined (QTIM and HCP) sample (hippocampal fissure (up to 6.79%), presubiculum (up to 3.08%), and hippocampal tail (up to −0.23%)). In contrast, no sex differences were detected for the volume of the cornu ammonis (CA)2/3, CA4, Hippocampus-Amygdala Transition Area (HATA), or the granule cell layer of the dentate gyrus (GCDG). These findings show that, independent of differences in HPV, there are regionally specific sex differences in the hippocampus, which may be most prominent in the fimbria and parasubiculum. Further, given sex differences were less consistent across cohorts after controlling for BSV, adjusting for HPV rather than BSV may benefit future studies. This work may help in disentangling sex effects, and provide a better understanding of the implications of sex differences for behaviour and neuropsychiatric disorders.

The cetacean hippocampal formation has been noted to be one of the smallest relative to brain size of all mammals studied. This region, comprised of the dentate gyrus, hippocampus proper, subiculum, presubiculum, parasubiculum and the entorhinal cortex, is important in learning, memory, and navigation. There have been a number of studies detailing the distribution of acetylcholinesterase (AChE) in the hippocampal formation of terrestrial mammals with the goal of gaining a greater understanding of some aspects of the cholinergic innervation to this region, as well as its parcellation. The present study was undertaken to describe the organization, cytoarchitecture, and distribution of AChE in the hippocampal formation of the Atlantic white-sided dolphin (AWSD) with the view to understand similarities and differences between this aquatic mammal and terrestrial mammals. Nissl-staining demonstrated cytoarchitecture of the hippocampal formation in the AWSD comparable to that reported in other cetaceans. In addition, the AWSD had a rich pattern of AChE staining that distinctly varied between regions and laminae. A number of differences in the distribution of AChE staining in areas comparable to those of terrestrial species reported suggested possible alterations in connectivity of this region. Overall, however, AChE-staining suggested that cholinergic innervation, neural pathways and function of the hippocampal formation of the AWSD is conserved, similar to other mammals.

To investigate the volumetric alterations of hippocampal subfields and identify which subfields contribute to mild cognitive impairment (MCI) in multiple system atrophy (MSA) and Parkinson’s disease (PD). Thirty MSA-MCI, 26 PD-MCI, and 30 healthy controls were administered cognitive assessment, along with hippocampal segmentation using FreeSurfer 6.0 after a 3-T MRI scan. Regression analyses were performed between the volumes of hippocampal subfields and cognitive variables. Compared with healthy controls, the volume of the hippocampal fissure was enlarged in PD-MCI patients, while left Cornu Ammonis (CA2–CA3), bilateral molecular layer, bilateral hippocampus–amygdala transition area, right subiculum, right CA1, right presubiculum, right parasubiculum, and bilateral whole hippocampus were reduced in the MSA-MCI group. Moreover, volumetric reductions of the bilateral hippocampal tail, bilateral CA1, bilateral presubiculum, bilateral molecular layer, left CA2–CA3, left hippocampus–amygdala transition area, right parasubiculum, and bilateral whole hippocampus were found in MSA-MCI relative to the PD-MCI group. The volumes of the left CA2–CA3 (B = − 11.34, p = 0.006) and left parasubiculum (B = 4.63, p = 0.01) were respectively correlated with language and abstraction functions. The volumes of the left fimbria (B = 6.99, p = 0.002) and left hippocampus–amygdala transition area (B = 2.28, p = 0.009) were correlated with visuospatial/executive function. The MSA-MCI patients showed more widespread impairment of hippocampal subfields compared with the PD-MCI group, involving trisynaptic loop and amygdala–hippocampus interactions. The alteration of CA, hippocampus–amygdala transition area, and fimbria still requires further comparison between the two patient groups. • The atrophy patterns of hippocampal subfields differed between MSA and PD patients. • MSA has widespread change in trisynaptic loop and amygdala–hippocampus interactions. • The atrophy patterns may help to understand the differences of cognitive impairment in MSA and PD.

Neurons in parasubiculum (PaS), presubiculum (PrS), and medial entorhinal cortex (MEC) code for place (grid cells) and head direction. Directional input has been shown to be important for stable grid cell properties in MEC, and PaS and PrS have been postulated to provide this information to MEC. In line with this, head direction cells in those brain areas are present at postnatal day 11 (P11), having directional tuning that stabilizes shortly after eye opening, which is before premature grid cells emerge in MEC at P16. Whether functional connectivity between these structures exists at those early postnatal stages is unclear. Using anatomical tracing, voltage-sensitive dye imaging and single-cell patch recordings in female and male rat brain slices between P2 and P61, we determined when the pathways from PaS and PrS to MEC emerge, become functional, and how they develop. Anatomical connections from PaS and PrS to superficial MEC emerge between P4 and P6. Monosynaptic connectivity from PaS and PrS to superficial MEC was measurable from P9 to P10 onward, whereas connectivity with deep MEC was measurable from P11 to P12. From P14/P15 on, reactivity of MEC neurons to parasubicular and presubicular inputs becomes adult-like and continues to develop until P28-P30. The maturation of the efficacy of both inputs between P9 and P21 is paralleled by maturation of morphological properties, changes in intrinsic properties of MEC principal neurons, and changes in the GABAergic network of MEC. In conclusion, synaptic projections from PaS and PrS to MEC become functional and adult-like before the emergence of grid cells in MEC.SIGNIFICANCE STATEMENTHead direction information, crucial for grid cells in medial entorhinal cortex (MEC), is thought to enter MEC via parasubiculum (PaS) and presubiculum (PrS). Unraveling the development of functional connections between PaS, PrS, and MEC is key to understanding how spatial navigation, an important cognitive function, may evolve. To gain insight into the development, we used anatomical tracing techniques, voltage-sensitive dye imaging, and single-cell recordings. The combined data led us to conclude that synaptic projections from PaS and PrS to MEC become functional and adult-like before eye opening, allowing crucial head direction information to influence place encoding before the emergence of grid cells in rat MEC.

Purpose MRI-negative epilepsy patients could benefit from advanced imaging techniques such as high-resolution diffusion magnetic resonance imaging (dMRI). Our aim was to perform hippocampal subfield-specific tractography and quantify connectivity of the subfields in MRI-negative patients. Abnormal connectivity of the hippocampal subfields may help inform seizure focus hypothesis and provide information to guide surgical intervention. Methods Hippocampal structural imaging and dMRI was acquired in 25 drug resistant MRI-negative patients and 25 healthy volunteers. The hippocampi of each subject was segmented on high-resolution structural images and dMRI-based probabilistic tractography was performed in each subfield. The degrees of connectivity and fiber densities of the hippocampal subfields were quantified and compared between epilepsy patients and healthy volunteers. Results We were able to perform subfield-specific hippocampal tractography in each subject that participated in this study. These methods identified some hippocampal subfields that are abnormally connected in MRI-negative patients. In particular patients suspected of left temporal seizure focus exhibited increased connectivity of certain ipsilateral subfields, especially the subiculum, presubiculum, and parasubiculum, and reduced connectivity of some contralateral subfields, such as CA1 and subiculum. Conclusions Our data suggest that the hippocampal subfields are connected in distinct ways in different types of epilepsy. These results may provide important information that could help inform seizure focus hypothesis and in the surgical treatment of MRI-negative patients. These observations suggest that high-resolution dMRI-based tractography of the hippocampal subfields can detect subtle abnormalities in otherwise normal-appearing MRI-negative patients.

Objective Attention-deficit hyperactivity disorder (ADHD) is accompanied by reduction of total hippocampal volume. However, disorder-related fine-grained structural alterations of hippocampal subfields remain unclear. Method Here we compared hippocampal subfield volumes in a large sample of patients with ADHD and healthy controls. We used T1-weighted structural 3-Tesla MRI images of 880 individuals (7–21 years old) from the ADHD-200 database. The images were acquired from 553 healthy individuals and 327 children and adolescents with combined (N = 196) and inattentive (N = 131) ADHD subtypes. Hippocampal subfields were segmented into the cornu amonis regions (CA1, CA2/3, CA4), fimbria, hippocampal fissure, presubiculum, subiculum, hippocampal tail, parasubiculum, granule cell layers of the dentate gyrus, molecular layer within the subiculum and the CA fields, and the hippocampal-amygdala transition area using an automatic algorithm available in Freesurfer 6.0. Results We found a significant reduction of total hippocampal volume in the combined ADHD group compared to healthy controls. This reduction was due to the atrophy of CA1, CA4, molecular layer, granule cell layers of the dentate gyrus, presubiculum, subiculum, and hippocampal tail. These differences were exclusively driven by the corresponding brain volume reduction in the combined ADHD-subtype, while hippocampal volumes in inattentive ADHD showed no reliable differences relative to controls. Finally, there were negative correlations between the reduced hippocampal subfields and behavioral ADHD indices. Conclusion The present results point to a clear dissociation between inattentive and combined subtypes of ADHD. Therefore, hippocampal subfields may contribute towards understanding the pathophysiology of ADHD.

Dong Woo Kang,1 Hyun Kook Lim,2 Soo-hyun Joo,1 Na Rae Lee,1 Chang Uk Lee1 1Department of Psychiatry, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 2Department of Psychiatry, Yeoui-do St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Objective: Previous research has indicated that there are potential associations between education and total hippocampal volume in the trajectory of Alzheimer’s disease (AD). However, the correlation between education and hippocampal subfield volumes in the progression of AD has yet to be understood. This study examined the relationship between education, which is a standard proxy for cognitive reserve, and hippocampal subfield volumes in healthy and amnestic mild cognitive impairment (aMCI) groups.Subjects and methods: Thirty-eight subjects with aMCI and 39 healthy control subjects underwent 3 T magnetic resonance imaging, and hippocampal subfield volumes were measured by automated segmentation. Multiple linear regression analysis was used to determine the association between education and hippocampal subfield volumes.Results: Education had a significant negative correlation with the left parasubiculum, presubiculum, and subiculum volumes in the aMCI group. In addition, multiple subfield volumes including left parasubiculum, left/right presubiculum, left cornus ammonis (CA)3, and left CA4 showed a significant correlation with the neuropsychological test scores in the control group and aMCI group.Conclusion: These findings contribute to a better understanding of the association between education, hippocampal subfield volumes, and amnestic cognitive functions in the early phase of AD. Keywords: education, hippocampus, presubiculum, subiculum, mild cognitive impairment, cognitive reserve

Secretagogin (SCGN) is a recently discovered calcium‐binding protein belonging to the group of EF‐hand calcium‐binding proteins. SCGN immunostaining has been described in various regions of the human, rat and mouse brain. In these studies, it has been reported that, in general, the patterns of SCGN staining differ between rodents and human brains. These differences have been interpreted as uncovering phylogenetic differences in SCGN expression. Nevertheless, an important aspect that is not usually taken into account is that different methods are used for obtaining and processing brain tissue coming from humans and experimental animals. This is a critical issue since it has been shown that post‐mortem time delay and the method of fixation (i.e., perfused vs. nonperfused brains) may influence the results of the immunostaining. Thus, it is not clear whether differences found in comparative studies with the human brain are simply due to technical factors or species‐specific differences. In the present study, we analyzed the pattern of SCGN immunostaining in the adult human hippocampal formation (DG, CA1, CA2, CA3, subiculum, presubiculum, and parasubiculum) as well as in the entorhinal and perirhinal cortices. This pattern of immunostaining was compared with rat and mouse that were fixed either by perfusion or immersion and with different post‐mortem time delays (up to 5 hr) to mimic the way the human brain tissue is usually processed. We found a number of clear similarities and differences in the pattern of labeling among the human, rat, and mouse in these brain regions as well as between the different brain regions examined within each species. These differences were not due to the fixation., Graphical abstract showing secretagogin immunostaining pattern in various regions of the human, rat, and mouse brain. Clear similarities and differences are found in the pattern of labeling among the human, rat, and mouse in the hippocampal formation and entorhinal and perirhinal cortices, as well as between the different brain regions examined within each species.

Für die meisten Säugetiere ist Navigation eine essentielle kognitive Fähigkeit. Im Bereich der Neurowissenschaften gab es immense Fortschritte im Verständnis neuronaler Grundlagen von Navigation. Diese Dissertation beschäftigt sich mit der neuronalen Grundlage von Navigation im Hinblick auf Hirnstruktur (d.h. Parasubikulum) und ethologisch relevante Verhaltensweisen (d.h. Heimkehr und Spielverhalten). Im ersten Kapitel konzentriere ich mich auf das Verhältnis von Struktur und Funktion im Parasubikulum. Wir postulieren, dass das Parasubikulum durch seine selektive Vernetzung mit dem entorhinalen Kortex, durch seine starke interne Konnektivität, sowie wegen dem hohen Grad räumlich selektiver Aktivitätsmuster seiner Neurone im Bezug auf die Kontrolle von Gitterzellaktivität und räumlicher Navigation eine herausragende Stellung einnimmt. Im zweiten Kapitel untersuche ich die neuronale Grundlage von Heimkehr. Wir nutzen die starke Verbundenheit von Laborratten zu ihrem Zuhause. Wir zeigen, dass das Parasubikulum und der entorhinale Kortex keinen expliziten Heimvektor besitzen und dass die Präsenz des Zuhauses keine globale Veränderung der neuralen Repräsentation des Raums hervorruft. Allerdings führte die Präsenz des Zuhauses oder anderer geometrischer Objekte zu einer Verzerrung von Gitterzellen. Im dritten Kapitel unteruche ich Navigation im Hinblick auf Spielverhalten. Ratten erlernen das Versteckspiel schnell und verhalten sich erstaunlich regelkonform. Zeigen Ratten spielspezifische Vokalisationen. Gleichzeitige Ableitungen neuronaler Aktivität im medialen präfrontalen Kortex offenbarten starke und spezifische Antworten der meisten Nervenzellen auf verschiedene Phasen des Spiels des spezifischen Spielkontextes wiederspiegeln. Diese Arbeit liefert durch ihren ethologischen Ansatz und durch Verhaltensanalysen von sich frei verhaltenden Tieren einen wichtigen Beitrag zum besseren Verständnis neuronaler Grundlagen von Navigation im Säugetiergehirn., Navigation is an essential cognitive skill in the life of most animals. Animals move along space to procure the advantages of different places in the environment, and to adapt to ever changing resources, dangers and needs. This thesis addresses the neural bases of navigation in the context of brain structure (i.e. the parasubiculum) and ethologically relevant behaviors (i.e. homing and playing). In the first chapter I focus on the structure function relation of the parasubiculum: an understudied area of the rat’s parahippocampal cortex. We performed the most comprehensive study of the parasubiculum up to date and propose that, because of its selective connectivity with the medial entorhinal cortex, its internal connectivity, and the high spatial and head directional tuning of its neurons, the parasubiculum sits in remarkable position to control grid cell activity and navigation. In the second chapter, I study the neural bases of homing. We use the lab-rat' s strong attachment to its home cage to study whether brains maintain an online home vector. We show, that the parasubiculum and medial entorhinal cortex do not have an explicit home vector representation, and that the presence of home did not affect global encoding of space. However, we do find that grid cells are distorted by the home or other geometrical features affecting the internal environment. In the third chapter, I study navigation in an interspecies role-playing game. We played 'Hide and Seek' with rats and found that they acquired the game easily and played by the rules. Rats were strategic and developed game specific vocalizations patterns. We recorded from the medial prefrontal cortex and found that neurons respond sharply to different phases of the game, and may encode as well the context in which this events take place. By emphasizing ethological approaches and free behaviors this thesis contributes to an increased understanding of the neural underpinnings of navigation in the mammalian brain.

The presubiculum plays a key role in processing and integrating spatial and head-directional information. Layer III neurons of the presubiculum provide strong projections to the superficial layers of the medial entorhinal cortex (MEC) in the rat. Our previous study revealed that the terminal distribution of efferents from layer III cells of the presubiculum was organized in a band-like fashion within the MEC, and the transverse axis of these zones ran parallel to the rhinal fissure. Identifying axonal branching patterns of layer III neurons of the presubiculum is important to further elucidate the functional roles of the presubiculum. In the present study, we visualized all axonal processes and terminal distributions of single presubicular layer III neurons in the rat, using in vivo injection of a viral vector expressing membrane-targeted palmitoylation site-attached green fluorescent protein (GFP). We found that layer III of the rat presubiculum comprised multiple types of neurons (n = 12) with characteristic patterns of axonal collateralization, including cortical projection neurons (n = 6) and several types of intrinsic connectional neurons (n = 6). Two of six cortical projection neurons provided two or three major axonal branches to the MEC and formed elaborate terminal arbors within the superficial layers of the MEC. The width and axis of the area of their terminal distribution resembled that of the band-like terminal field seen in our massive-scale observation. Two of the other four cortical projection neurons gave off axonal branches to the MEC and also to the subiculum, and each of the other two neurons sent axons to the subiculum or parasubiculum. Patterns of axonal arborization of six intrinsic connectional neurons were distinct from each other, with four neurons sending many axonal branches to both superficial and deep layers of the presubiculum and the other two neurons showing sparse axonal branches with terminations confined to layers III–V of the presubiculum. These data demonstrate that layer III of the rat presubiculum consists of multiple types of cortical projection neurons and interneurons, and also suggest that inputs from a single presubicular layer III neuron can directly affect a band-like zone of the MEC.