Optogenetic inhibition of the dorsal hippocampus CA3 region during early-stage cocaine-memory reconsolidation disrupts subsequent context-induced cocaine seeking in rats

The dorsal hippocampus (DH) is key to the long-term maintenance of cocaine memories following retrieval-induced memory destabilization; even though, it is not the site of protein synthesis-dependent memory reconsolidation. Here, we took advantage of the temporal and spatial specificity of an optogenetic manipulation to examine the role of the cornu ammonis 3 subregion of the DH (dCA3) in early-stage cocaine-memory reconsolidation. Male Sprague-Dawley rats expressing eNpHR3.0 in the DH were trained to self-administer cocaine in a distinct context and underwent extinction training in a different context. Rats then received a 15-min memory-reactivation session, to destabilize cocaine memories and trigger reconsolidation, or remained in their home cages (no-reactivation controls). Optogenetic inhibition of the dCA3 for 1 h immediately, but not 1 h, after memory reactivation resulted in cocaine-memory impairment as indicated by reduction in drug-seeking behavior selectively in the cocaine-paired context 3 d later, at test, relative to responding in no-inhibition, no-reactivation, and no-eNpHR3.0 controls. Cocaine-memory impairment was associated with reduced c-Fos expression, an index of neuronal activation, in the dCA3 stratum lucidum (SL) and stratum pyramidale (SP) at test. Based on these observations and extant literature, we postulate that recurrent circuits in the SP are activated during early-stage memory reconsolidation to maintain labile cocaine memories prior to protein synthesis-dependent restabilization in another brain region, such as the basolateral amygdala. Furthermore, SL and SP interneurons may enhance memory reconsolidation by limiting synaptic noise in the SP and also contribute to recall as elements of the updated cocaine engram or retrieval links.

Generation of Dystrophin Short Product-Specific Tag-Insertion Mouse: Distinct Dp71 Glycoprotein Complexes at Inhibitory Postsynapse and Glia Limitans

Duchenne muscular dystrophy (DMD), the most severe form of dystrophinopathies, is a fatal X-linked recessive neuromuscular disorder characterized by progressive muscle degeneration and various extents of intellectual disabilities. Physiological and pathological roles of the responsible gene, dystrophin, in the brain remain elusive due to the presence of multiple dystrophin products, mainly full-length dystrophin, Dp427, and the short product, Dp71. In this study, we generated a Dp71-specific hemagglutinin (HA) peptide tag-insertion mice to enable specific detection of intrinsic Dp71 expression by anti-HA tag antibodies. Immunohistochemical detections in the transgenic mice demonstrated Dp71 expression not only at the blood-brain barrier, where astrocytic endfeet surround the microvessels, but also at the inhibitory postsynapse of hippocampal dentate granule neurons. Interestingly, hippocampal cornu ammonis (CA)1 pyramidal neurons were negative for Dp71 although Dp427 detected by anti-dystrophin antibody was clearly present at the inhibitory postsynapse, suggesting cell-type dependent dystrophin expressions. Precise examination using the primary hippocampal culture validated exclusive localization of Dp71 at the inhibitory postsynaptic compartment but not at the excitatory synapse in neurons. We further performed interactome analysis and found that Dp71 formed distinct molecular complexes, i.e. synapse-associated Dp71 interacted with dystroglycan (Dg) and dystrobrevinb (Dtnb) whereas glia-associated Dp71 did with Dg and dystrobrevina (Dtna). Thus, our data indicates that Dp71 and its binding partners are relevant to the inhibitory postsynaptic function of hippocampal granule neurons and the novel Dp71-transgenic mouse provides a valuable tool to understand precise physiological expressions and functions of Dp71 and its interaction proteins in vivo and in vitro.

The Presence of the Temporal Horn Exacerbates the Vulnerability of Hippocampus during Head Impacts

Hippocampal injury is common in traumatic brain injury (TBI) patients, but the underlying pathogenesis remains elusive. In this study, we hypothesize that the presence of the adjacent fluid-containing temporal horn exacerbates the biomechanical vulnerability of the hippocampus. Two finite element models of the human head were used to investigate this hypothesis, one with and one without the temporal horn, and both including a detailed hippocampal subfield delineation. A fluid-structure interaction coupling approach was used to simulate the brain-ventricle interface, in which the intraventricular cerebrospinal fluid was represented by an arbitrary Lagrangian-Eulerian multi-material formation to account for its fluid behavior. By comparing the response of these two models under identical loadings, the model that included the temporal horn predicted increased magnitudes of strain and strain rate in the hippocampus with respect to its counterpart without the temporal horn. This specifically affected cornu ammonis (CA) 1 (CA1), CA2/3, hippocampal tail, subiculum, and the adjacent amygdala and ventral diencephalon. These computational results suggest the presence of the temporal horn is a predisposing factor for the prevalence of hippocampal injury, advancing the understanding of hippocampal injury during head impacts. A corresponding analysis in an imaging cohort of collegiate athletes found that temporal horn size negatively correlates with hippocampal volume in the same subfields, suggesting a possible real-world correlation whereby a larger temporal horn may be associated with decreased hippocampal volume. Our biomechanical and neuroimaging effort collectively highlight the mechanobiological and anatomical interdependency between the hippocampus and temporal horn.

Directional Tuning of Phase Precession Properties in the Hippocampus

Running direction in the hippocampus is encoded by rate modulations of place field activity but also by spike timing correlations known as theta sequences. Whether directional rate codes and the directionality of place field correlations are related, however, has so far not been explored and therefore the nature of how directional information is encoded in the cornu ammonis remains unresolved. Here, using a previously published dataset that contains the spike activity of rat hippocampal place cells in the CA1, CA2 and CA3 subregions during free foraging of male Long-Evans rats in a 2D environment, we found that rate and spike timing codes are related. Opposite to a place field's preferred firing rate direction spikes are more likely to undergo theta phase precession and, hence, more strongly impact paired correlations. Furthermore, we identified a subset of field pairs whose theta correlations are intrinsic in that they maintain the same firing order when the running direction is reversed. Both effects are associated with differences in theta phase distributions, and are more prominent in CA3 than CA1. We thus hypothesize that intrinsic spiking is most prominent when the directionally modulated sensory-motor drive of hippocampal firing rates is minimal, suggesting that extrinsic and intrinsic sequences contribute to phase precession as two distinct mechanisms.

Roles of apoptosis and autophagy in natural rabies infections

The aim of this study was to investigate the activity of apoptosis and autophagy in animals (cows, horses, donkeys, dogs and cats) naturally infected with rabies by using immunohistochemistry, immunofluorescence, and qPCR. The mRNA transcript levels of caspase-3, Bax, Bcl2 and LC3B were determined with qPCR. Caspase-3 and AIF immunopositivity were not observed in the immunohistochemical and immunofluorescence staining, whereas LC3B immunopositivity was determined intensively in the infected animals compared to the control groups. LC3B immunopositivity was detected in the cytoplasm of the Purkinje cells in the cerebellum of the cows, horses and donkeys, and also in the cytoplasm of the neurons in the cornu ammonis of the dogs and cats. While the expression levels of caspase-3 and Bax were downregulated, the Bcl2 expression was up-regulated in the infected animals compared to the uninfected animals. In addition, the LC3B levels were found to be significantly higher in the infected animals. To the best of our knowledge, this work represents the first report of neuronal death in the central nervous system by autophagy, rather than by caspase-dependent or AIF-containing caspase-independent apoptosis.

Heritability of hippocampal functional and microstructural organisation

The hippocampal formation is an uniquely infolded anatomical structure in the medial temporal lobe and it is involved in a broad range of cognitive and emotional processes. It consists of anatomically and functionally different subfields, including the subiculum (SUB), cornu ammonis areas (CA), and the dentate gyrus (DG). However, despite ample research on learning and plasticity of the hippocampal formation, heritability of its structural and functional organization is not fully known. To answer this question, we extracted microstructurally sensitive neuroimaging (i.e., T1w/T2w ratios) and resting-state functional connectivity information along hippocampal subfield surfaces from a sample of healthy twins and unrelated individuals of the Human Connectome Project Dataset. Our findings robustly demonstrate that functional connectivity and local microstructure of hippocampal subfields are highly heritable. Second, we found marked covariation and genetic correlation between the microstructure of the hippocampal subfields and the isocortex, indicating shared genetic factors influencing the microstructure of the hippocampus and isocortex. In both structural and functional measures, we observed a dissociation of cortical projections across subfields. In sum, our study shows that the functional and structural organization of the hippocampal formation is heritable and has a genetic relation to divergent macroscale functional networks within the isocortex.

Ex vivo MRI atlas of the human medial temporal lobe: characterizing neurodegeneration due to tau pathology

Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages.

Quantitative analysis of size and regional distribution of corpora amylacea in the hippocampal formation of obstructive sleep apnoea patients

Corpora amylacea (CoA) are spherical aggregates of glucose polymers and proteins within the periventricular, perivascular and subpial regions of the cerebral cortex and the hippocampal cornu ammonis (CA) subfields. The present study quantified the distribution of CoA in autopsied hippocampi of patients with obstructive sleep apnoea (OSA) using ethanolamine-induced fluorescence. CoA were observed in 29 of 30 patients (96.7%). They were most abundant in periventricular regions (wall of lateral ventricle, alveus, fimbria and CA4), rarely found in the CA3 and CA1, and undetectable in the CA2 or subiculum. A spatiotemporal sequence of CoA deposition was postulated, beginning in the fimbria and progressively spreading around the subpial layer until they extended medially to the wall of the lateral ventricle and laterally to the collateral sulcus. This ranked CoA sequence was positively correlated with CoA packing density (count and area fraction) and negatively correlated with CoA minimum diameters (p < 0.05). Although this sequence was not correlated with age or body mass index (BMI), age was positively correlated with the mean and maximum diameters of CoA. These findings support the view that the spatiotemporal sequence of CoA deposition is independent of age, and that CoA become larger due to the accretion of new material over time.

Hippocampal Metabolic Subregions and Networks: Behavioral, Molecular and Pathological Aging Profiles

Purpose: Hippocampal dysfunction happens across many neuropsychiatric disorders and is the hallmark of Alzheimer’s disease with evidenced metabolic alterations. However, while metabolic changes are a key aspect of Alzheimer’s disease, hippocampal metabolic networks, as defined by metabolic covariance, haven’t been identified in healthy populations. As the hippocampus portrays cytoarchitectural, connectional, and functional heterogeneity, heterogeneous patterns of metabolic covariance could be expected. Methods: We first characterized this heterogeneity with a data-driven approach by identifying the spatial pattern of hippocampus differentiation based on metabolic covariance with the rest of the brain in FDG-PET data of large healthy elderly cohort (n=362). Then, we characterized the metabolic networks of the robustly defined subregions. In the following, we characterized the disentangled hippocampal metabolic networks with regards to behavioral and neurotransmitter systems using quantitative decoding. Finally, we examined how the local metabolism in the hippocampal subregions is influenced by Alzheimer’s disease pathology in a cohort of ADNI participants (n = 580). Results: Based on hippocampal-brain metabolic covariance in a healthy elderly cohort, we found a differentiation into primarily anterior vs. posterior and secondarily Cornu Ammonis (CA) vs. subiculum subregions. Characterizing the associated metabolic networks revealed that the anterior-subiculum network including temporal-pole and orbitofrontal regions relates to self, motivation and mentalizing behavior and is influenced by dopaminergic systems. In contrast, the posterior-subiculum shows a wide cortical network engaged in action- and world-oriented cognition targeted by serotoninergic systems. The anterior- and posterior-CA, connected respectively to amygdala and broader subcortical networks, are associated to several transporters release. Local metabolism comparison between Alzheimer’s disease-related diagnosis groups revealed early CA’s alterations while posterior subicular alterations appear at advanced stages in line with broader cortical atrophy and behavioral dysfunctions.Conclusion: Future studies should delineate patients’ individual profiles according to hippocampal subregions and networks.