Hippocampal Longitudinal Axis Research Articles

Differential atrophy along the longitudinal hippocampal axis in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the hippocampus. Since hippocampal studies have highlighted a differential subregional regulation along its longitudinal axis, a more detailed analysis addressing subregional changes along the longitudinal hippocampal axis has the potential to provide new relevant biomarkers. This study included structural brain MRI data of 583 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitively normal (CN) subjects, mild cognitively impaired (MCI) subjects and AD patients were conveniently selected considering the age and sex match between clinical groups. Structural MRI acquisitions were pre-processed and analysed with a new longitudinal axis segmentation method, dividing the hippocampus in three subdivisions (anterior, intermediate, and posterior). When normalizing the volume of hippocampal sub-divisions to total hippocampus, the posterior hippocampus negatively correlates with age only in CN subjects (r= -.31). The longitudinal ratio of hippocampal atrophy (anterior sub-division divided by the posterior one) shows a significant increase with age only in CN (r= .25). Overall, in AD, the posterior hippocampus is predominantly atrophied early on. Consequently, the anterior/posterior hippocampal ratio is an AD differentiating metric at early disease stages with potential for diagnostic and prognostic applications.

Three-dimensional histology reveals dissociable human hippocampal long-axis gradients of Alzheimer's pathology.

Three-dimensional (3D) histology analyses are essential to overcome sampling variability and understand pathological differences beyond the dissection axis. We present Path2MR, the first pipeline allowing 3D reconstruction of sparse human histology without a magnetic resonance imaging (MRI) reference. We implemented Path2MR with post-mortem hippocampal sections to explore pathology gradients in Alzheimer's disease. Blockface photographs of brain hemisphere slices are used for 3D reconstruction, from which an MRI-like image is generated using machine learning. Histology sections are aligned to the reconstructed hemisphere and subsequently to an atlas in standard space. Path2MR successfully registered histological sections to their anatomic position along the hippocampal longitudinal axis. Combined with histopathology quantification, we found an expected peak of tau pathology at the anterior end of the hippocampus, whereas amyloid-beta (Aβ) displayed a quadratic anterior-posterior distribution. Path2MR, which enables 3D histology using any brain bank data set, revealed significant differences along the hippocampus between tau and Aβ. Path2MR enables three-dimensional (3D) brain reconstruction from blockface dissection photographs. This pipeline does not require dense specimen sampling or a subject-specific magnetic resonance (MR) image. Anatomically consistent mapping of hippocampal sections was obtained with Path2MR. Our analyses revealed an anterior-posterior gradient of hippocampal tau pathology. In contrast, the peak of amyloid-beta (Aβ) deposition was closer to the hippocampal body.

Shared and unique heritability of hippocampal subregion volumes in children and adults

Behavioral genetic analyses have not demonstrated robust, unique, genetic correlates of hippocampal subregion volume. Genetic differentiation of hippocampal longitudinal axis subregion volume has not yet been investigated in population-based samples, although this has been demonstrated in rodent and post-mortem human tissue work. The following study is the first population-based investigation of genetic factors that contribute to gray matter volume along the hippocampal longitudinal axis. Twin-based biometric analyses demonstrated that longitudinal axis subregions are associated with significant, unique, genetic variance, and that longitudinal axis subregions are also associated with significant shared, hippocampus-general, genetic factors. Our study’s findings suggest that genetic differences in hippocampal longitudinal axis structure can be detected in individual differences in gray matter volume in population-level research designs.

Cognitive function and the longitudinal hippocampal axis in mesial temporal sclerosis

ObjectiveThe relationship of preoperative memory deficits in patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS) to the distribution of neuronal loss is uncertain. Building on the material specificity theory, we tested the hypothesis that visual memory deficits are associated with posterior hippocampal atrophy, whereas verbal memory deficits are associated with anterior hippocampal atrophy. MethodsWe studied 22 adults with mTLE and HS, calculating hippocampal head, body, and tail volumes, correcting for estimated total intracranial volume, using automated segmentation. Preoperative memory ability was evaluated with the Wechsler Memory Scale (WMS-II: logical memory, verbal paired associates, family pictures, and faces subtests). We correlated memory ability with hippocampal division volumes using SPSS 26.1 (repeated measures ANOVAs, one-way ANOVAs, Pearson r correlations) for statistical analysis. ResultsWe found a significant main effect of hippocampal subdivision, reporting volumetric differences between the head, body, and tail. Pairwise comparisons reported that the hippocampal head had significantly greater volume than both the body and tail (p < 0.001). For both left and right focus groups, the ipsilateral hippocampi were significantly smaller than the contralateral.Linear regression reported a left hippocampal model (head, body, and tail volumes) predicted performance on logical memory with the left hippocampal tail volume being the strongest predictor. A right hippocampal model (head, body, and tail volumes) predicted memory ability for family pictures and verbal paired associates at a trend level. ConclusionsIpsilateral hippocampal head and tail seem more vulnerable to injury than the body in both the left and right mTLE. Our study suggests there may be functional differences along the hippocampal longitudinal axis, particularly for the left hippocampal tail with verbal memory. Our findings are consistent with material-specific right-left differences in memory processing.

Multi-scale goal distance representations in human hippocampus during virtual spatial navigation

Goal-directed navigation relies on both coarse and fine-grained coding of spatial distance between the current position of a navigating subject and a goal destination. However, the neural signatures underlying goal distance coding remain poorly understood. Using intracranial EEG recordings from the hippocampus of drug-resistant epilepsy patients who performed a virtual spatial navigation task, we found that the right hippocampal theta power was significantly modulated by goal distance and decreased with goal proximity. This modulation varied along the hippocampal longitudinal axis such that theta power in the posterior hippocampus decreased more strongly with goal proximity. Similarly, neural timescale, reflecting the duration across which information can be maintained, increased gradually from the posterior to anterior hippocampus. Taken together, this study provides empirical evidence for multi-scale spatial representations of goal distance in thehuman hippocampus and links the hippocampal processing of spatial information to its intrinsic temporal dynamics.

Differential ripple propagation along the hippocampal longitudinal axis.

Hippocampal ripples are highly synchronous neural events critical for memory consolidation and retrieval. A minority of strong ripples has been shown to be of particular importance in situations of increased memory demands. The propagation dynamics of strong ripples inside the hippocampal formation are, however, still opaque. We analyzed ripple propagation within the hippocampal formation in a large open-access dataset comprising 267 Neuropixel recordings in 49 awake, head-fixed mice. Surprisingly, strong ripples (top 10% in ripple strength) propagate differentially depending on their generation point along the hippocampal longitudinal axis. The septal hippocampal pole is able to generate longer ripples that engage more neurons and elicit spiking activity for an extended time even at considerable distances. Accordingly, a substantial portion of the variance in strong ripple duration (R² = 0.463) is explained by the ripple generation location on the longitudinal axis, in agreement with a possible distinctive role of the hippocampal septal pole in conditions of high-memory demand. Moreover, we observed that the location of the ripple generation has a significant impact on the spiking rate modulation of different hippocampal subfields, even before the onset of the ripple. This finding suggests that ripple generation location plays a crucial role in shaping the neural activity across the hippocampus.

Septotemporal variations in hippocampal value and outcome processing.

A large body of evidence indicates functional variations along the hippocampal longitudinal axis. To investigate whether and how value and outcome processing vary between the dorsal (DH) and the ventral hippocampus (VH), we examined neuronal activity and inactivation effects of the DH and VH in mice performing probabilistic classical conditioning tasks. Inactivation of either structure disrupts value-dependent anticipatory licking, and value-coding neurons are found in both structures, indicating their involvement in value processing. However, the DH neuronal population increases activity as a function of value, while the VH neuronal population is preferentially responsive to the highest-value sensory cue. Also, signals related to outcome-dependent value learning are stronger in the DH. VH neurons instead show rapid responses to punishment and strongly biased responses to negative prediction error. These findings suggest that the DH faithfully represents the external value landscape, whereas the VH preferentially represents behaviorally relevant, salient features of experienced events.

A novel histological staging of hippocampal sclerosis that is evident in gray matter loss in vivo.

Hippocampal sclerosis of aging (HS) is defined by end-stage histological findings, strongly associated with limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). We aimed to characterize features of early HS to refine the understanding of its role within combined pathology. We studied 159 brain donations from the multimodal Vallecas Alzheimer's Center Study. A staging system (0 to IV) was developed to account for HS progression and analyzed in relation to pre-mortem cognitive and magnetic resonance imaging (MRI) data. Our HS staging system displayed a significant correlation with disease duration, cognitive performance, and combined neuropathologies, especially with LATE. Two-level assessment along the hippocampal longitudinal axis revealed an anterior-posterior gradient of HS severity. In vivo MRI showed focally reduced hippocampal gray matter density as a function of HS staging. The association of this staging system with clinical progression and structural differences supports its utility in the characterization and potential in vivo monitoring of HS. The definition of hippocampal sclerosis of aging (HS) is currently limited to an end-stage pathological fingerprint. We characterize early HS histological features to define a complete staging system. The proposed staging displays a parallel but not identical progression to limbic-predominant age-related TAR DNA-binding protein 43 (TDP-43) encephalopathy (LATE). The proposed staging also reflects the expected demographic and cognitive differences associated with HS. In vivo magnetic resonance imaging (MRI) showed focal hippocampal gray matter loss as a function of HS staging.

Microglial diversity along the hippocampal longitudinal axis impacts synaptic plasticity in adult male mice under homeostatic conditions.

The hippocampus is a plastic brain area that shows functional segregation along its longitudinal axis, reflected by a higher level of long-term potentiation (LTP) in the CA1 region of the dorsal hippocampus (DH) compared to the ventral hippocampus (VH), but the mechanisms underlying this difference remain elusive. Numerous studies have highlighted the importance of microglia-neuronal communication in modulating synaptic transmission and hippocampal plasticity, although its role in physiological contexts is still largely unknown. We characterized in depth the features of microglia in the two hippocampal poles and investigated their contribution to CA1 plasticity under physiological conditions. We unveiled the influence of microglia in differentially modulating the amplitude of LTP in the DH and VH, showing that minocycline or PLX5622 treatment reduced LTP amplitude in the DH, while increasing it in the VH. This was recapitulated in Cx3cr1 knockout mice, indicating that microglia have a key role in setting the conditions for plasticity processes in a region-specific manner, and that the CX3CL1-CX3CR1 pathway is a key element in determining the basal level of CA1 LTP in the two regions. The observed LTP differences at the two poles were associated with transcriptional changes in the expression of genes encoding for Il-1, Tnf-α, Il-6, and Bdnf, essential players of neuronal plasticity. Furthermore, microglia in the CA1 SR region showed an increase in soma and a more extensive arborization, an increased prevalence of immature lysosomes accompanied by an elevation in mRNA expression of phagocytic markers Mertk and Cd68 and a surge in the expression of microglial outward K+ currents in the VH compared to DH, suggesting a distinct basal phenotypic state of microglia across the two hippocampal poles. Overall, we characterized the molecular, morphological, ultrastructural, and functional profile of microglia at the two poles, suggesting that modifications in hippocampal subregions related to different microglial statuses can contribute to dissect the phenotypical aspects of many diseases in which microglia are known to be involved.

Connectivity and synaptic features of hilar mossy cells and their effects on granule cell activity along the hippocampal longitudinal axis.

The hippocampus is an elongated brain structure which runs along a ventral-to-dorsal axis in rodents, corresponding to the anterior-to-posterior axis in humans. A glutamatergic cell type in the dentate gyrus (DG), the mossy cells (MCs), establishes extensive excitatory collateral connections with the DG principal cells, the granule cells (GCs), and inhibitory interneurons in both hippocampal hemispheres along the longitudinal axis. Although coupling of two physically separated GC populations via long-axis projecting MCs is instrumental for information processing, the connectivity and synaptic features of MCs along the longitudinal axis are poorly defined. Here, using channelrhodopsin-2 assisted circuit mapping, we showed that MC excitation results in a low synaptic excitation-inhibition (E/I) balance in the intralamellar (local) GCs, but a high synaptic E/I balance in the translamellar (distant) ones. In agreement with the differential E/I balance along the ventrodorsal axis, activation of MCs either enhances or suppresses the local GC response to the cortical input, but primarily promotes the distant GC activation. Moreover, activation of MCs enhances the spike timing precision of the local GCs, but not that of the distant ones. Collectively, these findings suggest that MCs differentially regulate the local and distant GC activity through distinct synaptic mechanisms. KEY POINTS: Hippocampal mossy cell (MC) pathways differentially regulate granule cell (GC) activity along the longitudinal axis. MCs mediate a low excitation-inhibition balance in intralamellar (local) GCs, but a high excitation-inhibition balance in translamellar (distant) GCs. MCs enhance the spiking precision of local GCs, but not distant GCs. MCs either promote or suppress local GC activity, but primarily promote distant GC activation.

Quantitative and qualitative evaluation of the hippocampal cytoarchitecture in adult cats with regard to the pathological diagnosis of hippocampal sclerosis

Cats are known to be affected by hippocampal sclerosis, potentially causing antiseizure drug(s) resistance. In order to lay the foundation for a standardized, systematic classification and diagnosis of this pathology in cats, this prospective study aimed at evaluating normal reference values of cellular densities and the cytoarchitecture of the feline hippocampus. Three transverse sections (head, body and tail) of each left hippocampus were obtained from 17 non-epileptic cats of different brachycephalic and mesocephalic breeds and age classes (range: 3–17 years). Histological (hematoxylin and eosin, Nissl) and immunohistochemical (NeuN, GFAP) staining was performed to investigate neuron and astroglial cell populations, as well as the layer thickness of the pyramidal cell layer and granule cell layer. Significant differences in neuronal density (in CA2-CA4 and the granule cell layer) and layer thickness (in CA1-CA3 and the granule cell layer) were evidenced throughout the longitudinal hippocampal axis (p<0.05); on the other hand, the astrocyte density did not differ. Moreover, reference ranges were defined for these parameters in the pyramidal cell layer and in the granule cell layer. The findings did not differ according to breed or age. In veterinary medicine these parameters have not been evaluated in cats so far. As surgical treatment may become a therapeutic option for cats with temporal lobe epilepsy, estimating normal values of the hippocampal cytoarchitecture will help in the standardized histopathological examination of resected hippocampal specimens to reach a diagnosis of hippocampal sclerosis.

Barques are generated in posterior hippocampus and phase reverse over lateral posterior hippocampal surface

ObjectiveTo investigate whether barques can be localized across the hippocampal longitudinal axis with sufficient specificity. MethodsWe identified 51 focal epilepsy patients implanted with a minimum of two electrodes – unilateral anterior and posterior - in either hippocampus. We used visual inspection of the intracranial electroencephalogram (iEEG) and 3D brain volume spectrum-based statistical parametric mapping (SPM) to localize barques. ResultsIn 18/51 patients (35.29%), barques were identified in 22/70 (31.42%) hippocampi. In all hippocampi (100%), barques were present in the posterior hippocampus, while 9 (40.90%) showed concurrent non-independent barque activity anteriorly (P < 0.0001). Statistical parametric mapping confirmed the posterior barque localization, with significant differences in t-values (t(27) = 8.08, P < 0.0001) and z-scores (t(24) = 6.85, P < 0.0001) between anterior and posterior hippocampal barque activity. Posterior lateral extrahippocampal contacts demonstrated phase reversals of positive polarity during barque activity (P = 0.0092, compared to anterior extrahippocampal contacts). ConclusionsThis study highlights the posterior hippocampal predominance of barques. Our findings are concordant with the posterior distribution of the scalp manifestation of barques as “14&6/sec positive spikes”. The posterio-lateral hippocampal barque phase reversal can explain the positive polarity of scalp 14&6/sec spikes. SignificanceUnderstanding the properties of barques is critical for the iEEG interpretation in epilepsy surgery evaluations that include the hippocampus.

Differential atrophy along the longitudinal hippocampal axis in Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder that primarily affects the hippocampus. Since hippocampal studies have highlighted a differential subregional regulation along its longitudinal axis, a more detailed analysis addressing subregional changes along the longitudinal hippocampal axis has the potential to provide new relevant biomarkers.MethodThis study analysed structural brain MRI data of 600 participants (aged 55‐92 years‐old) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Hippocampi of cognitively normal (CN) subjects (n=200), mild cognitively impaired (MCI) subjects (n=200) and AD patients (n=200) were segmented with Freesurfer v6.0 and sub‐segmented along its longitudinal axis in anterior, intermediate and posterior sub‐divisions using an in‐house algorithm.ResultTotal hippocampal volume normalized to intracranial volume (ICV) negatively correlated with age in all groups. Standardized residuals from the linear regression of normalized hippocampal volume by age were then calculated, showing that the mean relative atrophy corrected for the aging effect was higher in CN (µ = 0.54) than in MCI (µ = 0.13), and lower in AD (µ = ‐0.67), with significant differences between all groups (p &lt; .001 in all comparisons). Both anterior, intermediate and posterior hippocampus negatively correlate with age in all groups, with no significant differences between them. However, when normalizing to total hippocampus, only CN subjects show a significant positive correlation (r = 0.15, p = .03) between anterior sub‐division and age, and only CN (r = ‐0.27, p &lt; .001) and MCI (r = ‐0.18, p = .01) posterior hippocampus negatively correlate with age. The longitudinal ratio of hippocampal atrophy (anterior sub‐division divided by the posterior one) shows a significant increase with age in CN (r = 0.25, p &lt; .001) and MCI (r = 0.15, p = .04) but not in AD (r = ‐0.07, p = .35).ConclusionNormal aging affects the hippocampus differently along its longitudinal axis: its posterior aspect shows more atrophy and the anterior one becomes relatively more prominent. In AD, this antero‐posterior gradient is disrupted early on, and hippocampal atrophy occurs in a similar manner along its longitudinal axis from late‐adulthood to older ages.

Sex Differences and Estradiol Effects in MAPK and Akt Cell Signaling across Subregions of the Hippocampus

Introduction: Rapid effects of estrogens within the hippocampus of rodents are dependent upon cell-signaling cascades, and activation of these cascades by estrogens varies by sex. Whether these pathways are rapidly activated within the dentate gyrus (DG) and CA1 by estrogens across sex and the anatomical longitudinal axis has been overlooked. Methods: Gonadally intact female and male rats were given either vehicle or physiological systemic low (1.1 µg/kg) or high (37.3 µg/kg) doses of 17β-estradiol 30 min prior to tissue collection. To control for the effects of circulating estrogens, an additional group of female rats was ovariectomized (OVX) and administered 17β-estradiol. Brains were extracted, and tissue punches of the CA1 and DG were taken along the longitudinal hippocampal axis (dorsal and ventral) and analyzed for key mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) cascade phosphoproteins. Results: Intact females had higher Akt pathway phosphoproteins (pAkt, pGSK-3β, and pp70S6K) than males in the DG (dorsal and ventral) and lower pERK1/2 in the dorsal DG. Most effects of 17β-estradiol on cell signaling occurred in OVX animals. In OVX animals, 17β-estradiol increased cell signaling of MAPK and Akt phosphoproteins (pERK1/2, pJNK, pAkt, and pGSK-3β) in the CA1 and pERK1/2 and pJNK DG. Discussion/Conclusions: Systemic 17β-estradiol treatment rapidly alters phosphoprotein levels in the hippocampus, dependent on reproductive status, and intact females have greater expression of Akt phosphoproteins than that in intact males in the DG. These findings shed light on underlying mechanisms of sex differences in hippocampal function and response to interventions that affect MAPK or Akt signaling.

Age‐related functional connectivity along the hippocampal longitudinal axis

Accumulated evidence points toward a long-axis functional division of the hippocampus, with its anterior part primarily associated with emotional processes and the posterior with navigation and cognition. It is yet unclear, however, how functional connectivity between areas along the hippocampal longitudinal axis and other brain regions differ, and how they are affected by age. Applying an anatomically driven general linear model-based functional connectivity analysis on a large database of resting-state fMRI data, we demonstrate that independent of age, the posterior hippocampus is functionally connected primarily with sensory and motor areas, the middle hippocampus with the default mode network, and the anterior with limbic and prefrontal regions. Along with an age-related disintegration of intra-hippocampal BOLD signal uniformity, the middle and posterior sub-regions exhibit mostly decreases in their functional connectivity with cortical regions, whereas the anterior hippocampus and ventral striatum appear to become more synchronized with age. These findings indicate that long-axis hippocampal areas are tuned to particular functional networks, which do not age in a unified manner.

Gradient of electro-convulsive therapy\u2019s antidepressant effects along the longitudinal hippocampal axis

Despite decades of successful treatment of therapy-resistant depression and major scientific advances in the field, our knowledge about electro-convulsive therapy’s (ECT) mechanisms of action is still scarce. Building on strong empirical evidence for ECT-induced hippocampus anatomy changes, we sought to test the hypothesis that ECT has a differential impact along the hippocampus longitudinal axis. We acquired behavioural and brain anatomy magnetic resonance imaging (MRI) data in patients with depressive episode undergoing ECT (n = 9) or pharmacotherapy (n = 24) and healthy controls (n = 30) at two time points 3 months apart. Using whole-brain voxel-based statistical parametric mapping and topographic analysis focused on the hippocampus, we observed ECT-induced gradient of grey matter volume increase along the hippocampal longitudinal axis with predominant impact on its anterior portion. Clinical outcome measures showed strong correlations with both baseline volume and rate of ECT-induced change exclusively for the anterior, but not posterior hippocampus. We interpret our findings confined to the anterior hippocampus and amygdala as additional evidence of the regional specific impact of ECT that unfolds its beneficial effect on depression via the “limbic” system. Main limitations of the study are patients’ polypharmacy, heterogeneity of psychiatric diagnosis, and long-time interval between scans.

Functional connectivity abnormalities of the long-axis hippocampal subregions in schizophrenia during episodic memory

Past evidence suggests that hippocampal subregions, namely the anterior and posterior parts, may be engaged in distinct networks underlying the memory functions which may be altered in patients with schizophrenia. However, of the very few studies that have investigated the hippocampal longitudinal axis subdivisions functional connectivity in patients with schizophrenia, the majority was based on resting-state data, and yet, none aimed to examine these during an episodic memory task. A total of 41 patients with schizophrenia and 45 healthy controls were recruited for a magnetic resonance imaging protocol in which they performed an explicit memory task. Seed-based functional connectivity analysis was employed to assess connectivity abnormalities between hippocampal subregions and voxel-wise connectivity targets in patients with schizophrenia. We observed a significantly reduced connectivity between the posterior hippocampus and regions from the default mode network, but increased connectivity with the primary visual cortex, in patients with schizophrenia compared to healthy subjects. Increased connectivity between the anterior hippocampus and anterior temporal regions also characterized patients with schizophrenia. In the current study, we provided evidence and support for studying hippocampal subdivisions along the longitudinal axis in schizophrenia. Our results suggest that the abnormalities in hippocampal subregions functional connectivity reflect deficits in episodic memory that may be implicated in the pathophysiology of schizophrenia.

Distinct and Common Large-Scale Networks of the Hippocampal Long Axis in Older Age: Links to Episodic Memory and Dopamine D2 Receptor Availability.

The hippocampal longitudinal axis has been linked to dissociated functional networks relevant to episodic memory. However, the organization of axis-dependent networks and their relation to episodic memory in aging remains less explored. Moreover, age-related deterioration of the dopamine (DA) system, affecting memory and functional network properties, might constitute a source of reduced specificity of hippocampal networks in aging. Here, we characterized axis-dependent large-scale hippocampal resting-state networks, their relevance to episodic memory, and links to DA in older individuals (n = 170, 64–68 years). Partial least squares identified 2 dissociated networks differentially connected to the anterior and posterior hippocampus. These overlapped with anterior–temporal/posterior–medial networks in young adults, indicating preserved organization of axis-dependent connectivity in old age. However, axis-specific networks were overall unrelated to memory and hippocampal DA D2 receptor availability (D2DR) measured with [11C]-raclopride positron emission tomography. Further analyses identified a memory-related network modulated by hippocampal D2DR, equally connected to anterior–posterior regions. This network included medial frontal, posterior parietal, and striatal areas. The results add to the current understanding of large-scale hippocampal connectivity in aging, demonstrating axis-dependent connectivity with dissociated anterior and posterior networks, as well as a primary role in episodic memory of connectivity shared by regions along the hippocampalaxis.

Homologous laminar organization of the mouse and human subiculum

The subiculum is the major output component of the hippocampal formation and one of the major brain structures most affected by Alzheimer’s disease. Our previous work revealed a hidden laminar architecture within the mouse subiculum. However, the rotation of the hippocampal longitudinal axis across species makes it unclear how the laminar organization is represented in human subiculum. Using in situ hybridization data from the Allen Human Brain Atlas, we demonstrate that the human subiculum also contains complementary laminar gene expression patterns similar to the mouse. In addition, we provide evidence that the molecular domain boundaries in human subiculum correspond to microstructural differences observed in high resolution MRI and fiber density imaging. Finally, we show both similarities and differences in the gene expression profile of subiculum pyramidal cells within homologous lamina. Overall, we present a new 3D model of the anatomical organization of human subiculum and its evolution from the mouse.

Stress reduces both model-based and model-free neural computations during flexible learning

Stressful events are thought to impair the flexible adaptation to changing environments, yet the underlying mechanisms are largely unknown. Here, we combined computational modeling and functional magnetic resonance imaging (fMRI) to elucidate the neurocomputational mechanisms underlying stress-induced deficits in flexible learning. Healthy participants underwent a stress or control manipulation before they completed, in the MRI scanner, a Markov decision task, frequently used to dissociate model-based and model-free contributions to choice, with repeated reversals of reward contingencies. Our results showed that stress attenuated the behavioral sensitivity to reversals in reward contingencies. Computational modeling further indicated that stress specifically affected the use of value computations for subsequent action selection. This reduced application of learned information on subsequent behavior was paralleled by a stress-induced reduction in inferolateral prefrontal cortex activity during model-free computations. For model-based learning, stress decreased specifically posterior, but not anterior, hippocampal activity, pointing to a functional segregation of model-based processing and its modulation by stress along the hippocampal longitudinal axis. Our findings shed light on the mechanisms underlying deficits in flexible learning under stress and indicate that, in highly dynamic environments, stress may hamper both model-based and model-free contributions to adaptive behavior.