Hippocampal Formation Research Articles

The effect of sulforaphane on perinatal hypoxic-ischemic brain injury in rats.

Perinatal hypoxic-ischemic insult (HII) is one of the main devastating causes of morbidity and mortality in newborns. HII induces brain injury which evolves to neurological sequelae later in life. Hypothermia is the only therapeutic approach available capable of diminishing brain impairment after HII. Finding a novel therapeutic method to reduce the severity of brain injury and its consequences is critical in neonatology. The present paper aimed to evaluate the effect of sulforaphane (SFN) pre-treatment on glucose metabolism, neurodegeneration, and functional outcome at the acute, sub-acute, and sub-chronic time intervals in the experimental model of perinatal hypoxic-ischemic insult in rats. To estimate the effect of SFN on brain glucose uptake we have performed 18F-deoxyglucose (FDG) microCT/PET. The activity of FDG was determined in the hippocampus and sensorimotor cortex. Neurodegeneration was assessed by histological analysis of Nissl-stained brain sections. To investigate functional outcomes a battery of behavioral tests was employed. We have shown that although SFN possesses a protective effect on glucose uptake in the ischemic hippocampus 24 h and 1 week after HII, no effect has been observed in the motor cortex. We have further shown that the ischemic hippocampal formation tends to be thinner in HIE and SFN treatment tends to reverse this pattern. We have observed subtle chronic movement deficit after HII detected by ladder rung walking test with no protective effect of SFN. SFN should be thus considered as a potent neuroprotective drug with the capability to interfere with pathophysiological processes triggered by perinatal hypoxic-ischemic insult.

The liver X receptors agonist GW3965 attenuates depressive-like behaviors and suppresses microglial activation and neuroinflammation in hippocampal subregions in a mouse depression model.

Liver X receptors (LXRs) have recently been reported to be novel and potential targets for the reversal of depressive-like behaviors, but the mechanism remains unclear. Hippocampal neuroinflammation and impairment of the normal structure and function of microglia are closely associated with depression. To investigate the effects of LXRs agonist (GW3965) on neuroinflammation and microglia in the hippocampal formation of mice with chronic unpredictable stress (CUS)-induced depression, depressive-like behaviors were evaluated by behavioral tests, hippocampal LXRs gene expression were evaluated by qRT-PCR, the protein expression levels of interleukin-1β, tumor necrosis factor-α, inducible nitric oxide synthase, nuclear factor kappa B, and cluster of differentiation 206 were estimated by western blotting, modern stereological methods were used to precisely quantify the total number of microglia in each hippocampal subregion, and immunofluorescence was used to detect the density of activated microglia and the morphology of microglia. We found that GW3965 alleviated the depressive-like behavior induced by CUS, reversed the decrease in hippocampal LXRα and LXRβ induced by CUS, increased the protein expression of pro-inflammatory factors, and decreased the protein expression of antiinflammatory factors induced by CUS. Moreover, CUS intervention significantly increased the number of microglia in the CA1 region, CA2/3 region, and dentate gyrus and the density of activated microglia in the CA2/3 region and dentate gyrus and significantly decreased the endpoints of microglial branches and process length of microglia in the dentate gyrus, while 4weeks of injections with GW3965 reversed these changes. These findings suggest that regulating the number, activated state, and morphology of microglia in hippocampal subregions might be an important basis for the antidepressant effects of LXRs.

Mnemonic construction and representation of temporal structure in the hippocampal formation

The hippocampal-entorhinal region supports memory for episodic details, such as temporal relations of sequential events, and mnemonic constructions combining experiences for inferential reasoning. However, it is unclear whether hippocampal event memories reflect temporal relations derived from mnemonic constructions, event order, or elapsing time, and whether these sequence representations generalize temporal relations across similar sequences. Here, participants mnemonically constructed times of events from multiple sequences using infrequent cues and their experience of passing time. After learning, event representations in the anterior hippocampus reflected temporal relations based on constructed times. Temporal relations were generalized across sequences, revealing distinct representational formats for events from the same or different sequences. Structural knowledge about time patterns, abstracted from different sequences, biased the construction of specific event times. These findings demonstrate that mnemonic construction and the generalization of relational knowledge combine in the hippocampus, consistent with the simulation of scenarios from episodic details and structural knowledge.

The E3 Ubiquitin Ligase CRL5 Regulates Dentate Gyrus Morphogenesis, Adult Neurogenesis, and Animal Behavior.

The dentate gyrus (DG) is an essential part of the hippocampal formation and participates in the majority of hippocampal functions. The DG is also one of the few structures in the mammalian central nervous system that produces adult-born neurons and, in humans, alterations in adult neurogenesis are associated with stress and depression. Given the importance of DG in hippocampal function, it is imperative to understand the molecular mechanisms driving DG development and homeostasis. The E3 ubiquitin ligase Cullin-5/RBX2 (CRL5) is a multiprotein complex involved in neuron migration and localization in the nervous system, but its role during development and in the adult DG remain elusive. Here, we show that CRL5 participates in mossy fiber pruning, DG layering, adult neurogenesis, and overall physical activity in mice. During DG development, RBX2 depletion causes an overextension of the DG mossy fiber infrapyramidal bundle (IPB). We further demonstrate that the increased activity in Reelin/DAB1 or ARF6 signaling, observed in RBX2 knockout mice, is not responsible for the lack of IPB pruning. Knocking out RBX2 also affects granule cell and neural progenitor localization and these defects were rescued by downregulating the Reelin/DAB1 signaling. Finally, we show that absence of RBX2 increases the number neural progenitors and adult neurogenesis. Importantly, RBX2 knockout mice exhibit higher levels of physical activity, uncovering a potential mechanism responsible for the increased adult neurogenesis in the RBX2 mutant DG. Overall, we present evidence of CRL5 regulating mossy fiber pruning and layering during development and opposing adult neurogenesis in the adult DG.

Distributed genetic architecture across the hippocampal formation implies common neuropathology across brain disorders

Despite its major role in complex human functions across the lifespan, most notably navigation, learning and memory, much of the genetic architecture of the hippocampal formation is currently unexplored. Here, through multivariate genome-wide association analysis in volumetric data from 35,411 white British individuals, we reveal 177 unique genetic loci with distributed associations across the hippocampal formation. We identify genetic overlap with eight brain disorders with typical onset at different stages of life, where common genes suggest partly age- and disorder-independent mechanisms underlying hippocampal pathology.

Considering the Role of Extracellular Matrix Molecules, in Particular Reelin, in Granule Cell Dispersion Related to Temporal Lobe Epilepsy.

The extracellular matrix (ECM) of the nervous system can be considered as a dynamically adaptable compartment between neuronal cells, in particular neurons and glial cells, that participates in physiological functions of the nervous system. It is mainly composed of carbohydrates and proteins that are secreted by the different kinds of cell types found in the nervous system, in particular neurons and glial cells, but also other cell types, such as pericytes of capillaries, ependymocytes and meningeal cells. ECM molecules participate in developmental processes, synaptic plasticity, neurodegeneration and regenerative processes. As an example, the ECM of the hippocampal formation is involved in degenerative and adaptive processes related to epilepsy. The role of various components of the ECM has been explored extensively. In particular, the ECM protein reelin, well known for orchestrating the formation of neuronal layer formation in the cerebral cortex, is also considered as a player involved in the occurrence of postnatal granule cell dispersion (GCD), a morphologically peculiar feature frequently observed in hippocampal tissue from epileptic patients. Possible causes and consequences of GCD have been studied in various in vivo and in vitro models. The present review discusses different interpretations of GCD and different views on the role of ECM protein reelin in the formation of this morphological peculiarity.

Impaired Functional Homotopy and Topological Properties Within the Default Mode Network of Children With Generalized Tonic-Clonic Seizures: A Resting-State fMRI Study.

IntroductionThe aim of the present study was to examine interhemispheric functional connectivity (FC) and topological organization within the default-mode network (DMN) in children with generalized tonic-clonic seizures (GTCS).MethodsResting-state functional MRI was collected in 24 children with GTCS and 34 age-matched typically developing children (TDC). Between-group differences in interhemispheric FC were examined by an automated voxel-mirrored homotopic connectivity (VMHC) method. The topological properties within the DMN were also analyzed using graph theoretical approaches. Consistent results were detected and the VMHC values were extracted as features in machine learning for subject classification.ResultsChildren with GTCS showed a significant decrease in VMHC in the DMN, including the hippocampal formation (HF), lateral temporal cortex (LTC), and angular and middle frontal gyrus. Although the patients exhibited efficient small-world properties of the DMN similar to the TDC, significant changes in regional topological organization were found in the patients, involving the areas of the bilateral temporal parietal junction, bilateral LTC, left temporal pole, and HF. Within the DMN, disrupted interhemispheric FC was found between the bilateral HF and LTC, which was consistent with the VMHC results. The VMHC values in bilateral HF and LTC were significantly correlated with clinical information in patients. Support vector machine analysis using average VMHC information in the bilateral HF and LTC as features achieved a correct classification rate of 89.34% for the classification.ConclusionThese results indicate that decreased homotopic coordination in the DMN can be used as an effective biomarker to reflect seizure effects and to distinguish children with GTCSs from TDC.

Impaired Grid-Like Representations at Theta Frequency in Schizophrenia

AimsSchizophrenia is a chronic brain disorder characterised by distortion of thoughts and perception. Several studies have shown a key role of the hippocampal formation in the pathophysiology of schizophrenia. Patients show impaired theta coherence between medial temporal lobe and medial prefrontal cortex (mPFC), and impairment of knowledge structuring and inferential processes. Both the hippocampal formation and mPFC contain hexadirectional modulation of activity, indicative of grid cell populations. Grid cells play an important role in mapping the environment and are believed to represent the transition structure between task states. With other cell populations in the hippocampal formation, they play a fundamental role in inference, episodic memory, and spatial navigation. Here, we investigate whether schizophrenia is associated with disrupted grid firing patterns.MethodsTo test this hypothesis, we asked 18 participants with diagnoses of schizophrenia and 26 controls (matched for age, sex and IQ) to perform a spatial memory task in magnetoencephalography (MEG), while navigating a virtual reality environment. We first analysed theta (4–10 Hz) power during movement onset compared to stationary periods. We then source-localised the signal and looked for the hexadirectional modulation of theta band oscillatory activity by heading direction during movement onset. We also controlled for other symmetries in theta frequencies (four, five, and eight fold) and hexadirectional modulation in other frequencies. The same participants performed an inference task outside MEG, which we used for correlation analysis.ResultsThe peak of theta power during movement onset was stronger in controls compared to patients (p < 0.05). In the control group, we found hexadirectional modulation of theta power by movement direction in the right entorhinal cortex (p < 0.005). This effect was absent in patients with a significant difference between groups (p < 0.05), suggesting that their entorhinal grid firing patterns may be disrupted. No other symmetry modulated theta power significantly in controls or patients, and hexadirectional modulation during movement onset was found only in theta frequencies in controls. Performance in the inference task was significantly impaired in schizophrenic patients, and spatial memory performance in both controls and patients was positively correlated with their performance in the inference task.ConclusionThese results are consistent with the hypothesis that impairments in knowledge structuring and inference associated with schizophrenia may arise from disrupted grid firing patterns in entorhinal cortex. Although further work is needed to better understand the role of grid cells in health and disease, this work provides new insights into dysfunction of the hippocampal formation in schizophrenia.

Genetic Specificity of Hippocampal Subfield Volumes, Relative to Hippocampal Formation, Identified in 2148 Young Adult Twins and Siblings.

The hippocampus is a complex brain structure with key roles in cognitive and emotional processing and with subregion abnormalities associated with a range of disorders and psychopathologies. Here we combine data from two large independent young adult twin/sibling cohorts to obtain the most accurate estimates to date of genetic covariation between hippocampal subfield volumes and the hippocampus as a single volume. The combined sample included 2148 individuals, comprising 1073 individuals from 627 families (mean age = 22.3 years) from the Queensland Twin IMaging (QTIM) Study, and 1075 individuals from 454 families (mean age = 28.8 years) from the Human Connectome Project (HCP). Hippocampal subfields were segmented using FreeSurfer version 6.0 (CA4 and dentate gyrus were phenotypically and genetically indistinguishable and were summed to a single volume). Multivariate twin modeling was conducted in OpenMx to decompose variance into genetic and environmental sources. Bivariate analyses of hippocampal formation and each subfield volume showed that 10%-72% of subfield genetic variance was independent of the hippocampal formation, with greatest specificity found for the smaller volumes; for example, CA2/3 with 42% of genetic variance being independent of the hippocampus; fissure (63%); fimbria (72%); hippocampus-amygdala transition area (41%); parasubiculum (62%). In terms of genetic influence, whole hippocampal volume is a good proxy for the largest hippocampal subfields, but a poor substitute for the smaller subfields. Additive genetic sources accounted for 49%-77% of total variance for each of the subfields in the combined sample multivariate analysis. In addition, the multivariate analyses were sufficiently powered to identify common environmental influences (replicated in QTIM and HCP for the molecular layer and CA4/dentate gyrus, and accounting for 7%-16% of total variance for 8 of 10 subfields in the combined sample). This provides the clearest indication yet from a twin study that factors such as home environment may influence hippocampal volumes (albeit, with caveats).

The brain of the tree pangolin (Manis tricuspis). IX. The pallial telencephalon.

A cyto‐, myelo‐, and chemoarchitectonic analysis of the pallial telencephalon of the tree pangolin is provided. As certain portions of the pallial telencephalon have been described previously (olfactory pallium, hippocampal formation, and amygdaloid complex), we focus on the claustrum and endopiriform nuclear complex, the white matter and white matter interstitial cells, and the areal organization of the cerebral cortex. Our analysis indicates that the organization of the pallial telencephalon of the tree pangolin is similar to that observed in many other mammals, and specifically quite similar to the closely related carnivores. The claustrum of the tree pangolin exhibits a combination of insular and laminar architecture, while the endopiriform nuclear complex contains three nuclei, both reminiscent of observations made in other mammals. The population of white matter interstitial cells resembles that observed in other mammals, while a distinct laminated organization of the intracortical white matter was revealed with parvalbumin immunostaining. The cerebral cortex of the tree pangolin presented with indistinct laminar boundaries as well as pyramidalization of the neurons in both layers 2 and 4. All cortical regions typically found in mammals were present, with the cortical areas within these regions often corresponding to what has been reported in carnivores. Given the similarity of the organization of the pallial telencephalon of the tree pangolin to that observed in other mammals, especially carnivores, it would be reasonable to assume that the neural processing afforded the tree pangolin by these structures does not differ dramatically to that of other mammals.

Resting state effective connectivity abnormalities of the Papez circuit and cognitive performance in multiple sclerosis.

The Papez circuit is central to memory and emotional processes. However, little is known about its involvement in multiple sclerosis (MS). We aimed to investigate abnormalities of resting state (RS) effective connectivity (EC) between regions of the Papez circuit in MS and their relationship with cognitive performances. Sixty-two MS patients and 64 healthy controls (HC) underwent neuropsychological assessment, 3D T1-weighted, and RS functional MRI. RS EC analysis was performed using SPM12 and dynamic causal modeling. RS EC abnormalities were investigated using parametric empirical Bayes models and were correlated with cognitive scores. Compared to HC, MS patients showed (posterior probability > 0.95) higher EC between the right entorhinal cortex and right subiculum, and lower EC from the anterior cingulate cortex (ACC) to the posterior cingulate cortex (PCC), from left to right subiculum, from left anterior thalamus to ACC, and within ACC and PCC. Lower RS EC from the ACC to the PCC correlated with worse global cognitive scores (rho = 0.19; p = 0.03), worse visuospatial memory (rho = 0.19; p = 0.03) and worse semantic fluency (rho = 0.21; p = 0.02). Lower RS EC from the left to the right subiculum correlated with worse verbal memory (rho = 0.20; p = 0.02), lower RS EC within the ACC correlated with worse attention (rho = -0.19; p = 0.04) and more severe brain atrophy (rho = -0.26; p = 0.003). Higher EC from the right entorhinal cortex to right subiculum correlated with worse semantic fluency (rho = 0.21; p = 0.02). In conclusion, MS patients showed altered RS EC within the Papez circuit. Abnormal RS EC involving cingulate cortices and hippocampal formation contributed to explain cognitive deficits.

0114 Evolution of brain circuits supporting spatial navigational memory across sleep

Abstract Introduction Systems consolidation is one of the major theories of sleep’s function in memory. Sleep is thought to be important in integrating and distributing hippocampal information to cortical structures such that there is less hippocampal activation, while at the same time increasing striatal activation, upon subsequent experience in the same environment that co-occurs with improved performance. Here we sought to examine the evidence supporting systems consolidation across sleep in spatial navigational memory. Methods 15 subjects (28±5 yrs., 8 female) with no prior videogame experience and no sleep disorders were recruited to undergo spatial navigational memory testing before and after a night of sleep. Spatial navigational memory was tested across two functional MR (fMRI) sessions (approx. 7PM and 8AM) separated by in-lab nocturnal polysomnography (NPSG) measured sleep using a virtual 3D Maze. Each fMRI session consisted of six runs: three maze trials interleaved with three control trials. During maze trials participants were instructed to reach a prespecified goal as quickly as possible, whereas during the control trials, participants were instructed to navigate a Z-shaped corridor with no prespecified goal. fMRI data was analyzed in 2-step procedure using Analysis of Functional Neuroimages (AFNI) software package. To estimate hippocampal activity during fMRI, parameter estimates of the %change in blood-oxygen-level-dependent (BOLD) signal using the contrast maze-control were used as the primary metric. Regions of interest were limited to the bilateral hippocampus, parahippocampal gyrus, caudate, and putamen using the Eickhoff-Zilles macro labels from the MNI-N27 template. Results During in-lab NPSG, participants experienced a total sleep time of 6.1±1.1 hrs (8.7±2.9%stage1, 51.2±7.6%stage2, 21.8±8.5%stage3, 18.1±6%REM). Within subjects, compared to pre-sleep, a significantly lower activation of the bilateral hippocampus and parahippocampal gyrus was observed post-sleep (evening-morning %change=0.26±0.11, p<0.05). Compared to pre-sleep, caudate and putamen activity was not significantly different post-sleep (evening-morning %change=-0.02±0.04,p=0.5). Greater evening hippocampal activity was associated with greater change in maze completion times across sleep (rho=0.54, p=0.04). Conclusion In young healthy adults, a night of uninterrupted sleep supports redistribution of hippocampal contribution toward spatial navigation. Greater initial pre-sleep hippocampal contribution was associated with improved recall of spatial navigational memory after a night of sleep. Support (If Any) NIH R21AG059179, R01AG056682, K25HL151912

Experience-Dependent Egr1 Expression in the Hippocampus of Japanese Quail.

The hippocampal formation (HF) is a structure critical to navigation and many forms of memory. In mammals, the firing of place cells is widely regarded as the fundamental unit of HF information processing. Supporting homology between the avian and mammalian HF, context-specific patterns of Egr1 have been reported in birds that are comparable to those produced by place cell firing in mammals. Recent electrophysiological data, however, suggest that many avian species lack place cells, potentially undermining the correspondence between Egr1 and place cell-related firing in the avian brain. To clarify this, the current study examines Egr1 expression in Japanese quail under conditions known to elicit only weakly spatially modulated firing patterns and report robust context-dependent Egr1 expression. These data confirm that context-dependent expression of Egr1 is not dependent on precise place fields and provide insight into how these birds are able to perform complex spatial tasks despite lacking mammalian-like place cells.

Blocking the dopaminergic receptors in the hippocampal dentate gyrus reduced the stress-induced analgesia in persistent inflammatory pain in the rat

Although the dentate gyrus (DG) as a component of the hippocampal formation has been well known for its role in memory, various studies showed a diverse population of unique cell types and various inputs and outputs in this region. Besides, brain dopamine is known for its roles in reward, motivation, pleasure, and being involved in the pain process. Further, previous studies demonstrated the participation of DG dopaminergic receptors in antinociception induced by lateral hypothalamus stimulation. This study aimed to investigate the role of DG dopaminergic receptors (D1- and D2-like dopamine receptors) in stress-induced analgesia (SIA) using the formalin test as a persistent inflammatory pain model. One hundred two male Wistar rats were unilaterally implanted with a cannula into the DG. Animals received an intra-DG infusion of SCH23390 (0.25, 1, and 4 μg/rat), or Sulpiride (0.25, 1, and 4 μg/rat) as D1- and D2-like dopamine receptor antagonists, respectively, five min before exposure to forced swim stress (FSS). Ten minutes after FSS termination, 2.5% formalin solution as an inflammatory agent was subcutaneously injected into the plantar surface of the hind paw, and the pain score was quantified for one hour. The findings revealed that exposure to FSS produced SIA, though this FSS-induced analgesia was attenuated in the early and late phase of the formalin test by intra-DG microinjection of SCH23390 or Sulpiride. These results suggested that both D1- and D2-like dopamine receptors in the DG have a considerable role in analgesia induced by FSS.

Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models.

Schizophrenia is a grave neuropsychiatric disease which frequently onsets between the end of adolescence and the beginning of adulthood. It is characterized by a variety of neuropsychiatric abnormalities which are categorized into positive, negative and cognitive symptoms. Most therapeutical strategies address the positive symptoms by antagonizing D2-dopamine-receptors (DR). However, negative and cognitive symptoms persist and highly impair the life quality of patients due to their disabling effects. Interestingly, hippocampal deviations are a hallmark of schizophrenia and can be observed in early as well as advanced phases of the disease progression. These alterations are commonly accompanied by a rise in neuronal activity. Therefore, hippocampal formation plays an important role in the manifestation of schizophrenia. Furthermore, studies with animal models revealed a link between environmental risk factors and morphological as well as electrophysiological abnormalities in the hippocampus. Here, we review recent findings on structural and functional hippocampal abnormalities in schizophrenic patients and in schizophrenia animal models, and we give an overview on current experimental approaches that especially target the hippocampus. A better understanding of hippocampal aberrations in schizophrenia might clarify their impact on the manifestation and on the outcome of this severe disease.

Global Exploration of RNA-Binding Proteins in Exercise-Induced Adult Hippocampal Neurogenesis: A Transcriptome Meta-analysis and Computational Study.

Voluntary physical exercise is a robust enhancer of adult hippocampal neurogenesis (AHN). A complete understanding of the molecular regulation of AHN is important in order to exploit the benefits of the process toward therapeutic approaches. Several factors such as epigenetic modifiers, non-coding RNAs, and transcription factors have been reported to regulate AHN. However, there is a limited understanding of the impact of RNA-binding proteins (RBPs) on exercise-mediated AHN, in spite of their well-documented significance in embryonic neurogenesis. The present study is the first global analysis to catalog the potential RBPs influencing exercise-mediated AHN. Here, a transcriptome meta-analysis was conducted to study exercise-mediated gene expression modulation in hippocampi of adult mice. Next, potential RBPs influencing transcriptome-wide expression changes via untranslated regions (UTRs) were identified. Among other RBPs, MATR3, Musashi, TIA1, and FXR2 (known critical modulators of neurogenesis) were found to potentially regulate gene expression patterns. Subsequently, binding sites of known neurogenesis-regulating RBPs were identified in the UTRs of AHN-associated genes modulated by exercise. Finally, a number of RBPs including RBFOX1, RBFOX3, and QKI (known regulators of neurogenesis) were found to be highly expressed in mouse hippocampal formation and also potentially interact with other RBPs, suggesting their combinatorial functioning in exercise-induced AHN. Thus, the present meta-analysis-based computational study identified several RBPs potentially important in exercise-induced AHN, which could form a foundation for further experiments to unravel RBP-mediated regulation of AHN.

Behavioral Training Related Neurotransmitter Receptor Expression Dynamics in the Nidopallium Caudolaterale and the Hippocampal Formation of Pigeons.

Learning and memory are linked to dynamic changes at the level of synapses in brain areas that are involved in cognitive tasks. For example, changes in neurotransmitter receptors are prerequisite for tuning signals along local circuits and long-range networks. However, it is still unclear how a series of learning events promotes plasticity within the system of neurotransmitter receptors and their subunits to shape information processing at the neuronal level. Therefore, we investigated the expression of different glutamatergic NMDA (GRIN) and AMPA (GRIA) receptor subunits, the GABAergic GABARG2 subunit, dopaminergic DRD1, serotonergic 5HTR1A and noradrenergic ADRA1A receptors in the pigeon’s brain. We studied the nidopallium caudolaterale, the avian analogue of the prefrontal cortex, and the hippocampal formation, after training the birds in a rewarded stimulus-response association (SR) task and in a simultaneous-matching-to-sample (SMTS) task. The results show that receptor expression changed differentially after behavioral training compared to an untrained control group. In the nidopallium caudolaterale, GRIN2B, GRIA3, GRIA4, DRD1D, and ADRA1A receptor expression was altered after SR training and remained constantly decreased after the SMTS training protocol, while GRIA2 and DRD1A decreased only under the SR condition. In the hippocampal formation, GRIN2B decreased and GABARG2 receptor expression increased after SR training. After SMTS sessions, GRIN2B remained decreased, GABARG2 remained increased if compared to the control group. None of the investigated receptors differed directly between both conditions, although differentially altered. The changes in both regions mostly occur in favor of the stimulus response task. Thus, the present data provide evidence that neurotransmitter receptor expression dynamics play a role in the avian prefrontal cortex and the hippocampal formation for behavioral training and is uniquely, regionally and functionally associated to cognitive processes including learning and memory.

Maternal Zika Virus Infection Alters Offspring Hippocampal Glycan Sulfation Patterns in Nonhuman Primates

Zika virus (ZIKV) infection during pregnancy can impair offspring hippocampal neurocircuit formation and cognitive function, but underlying mechanisms driving this neuronal miswiring remain unknown. During fetal development, axonal migration, pathfinding, and synaptogenesis are strongly influenced by extracellular chondroitin and dermatan sulfate‐glycosaminoglycans (CS/DS‐GAGs), which consist of six differentially sulfated isomers (CS‐A, B (DS), C, D, E, O). The relative abundance of these CS/DS isomers can influence functions ranging from circuit plasticity (CS‐C) and maturation (CS‐A, B) to axonal growth attraction (CS‐D) and repulsion (CS‐E). Using LC‐MS/MS to analyze the relative abundance of each CS/DS isomer in cortical and hippocampal tissue obtained from normal 145d fetal Macaca nemestrina nonhuman primates (NHP), a key difference between cortex and hippocampus included the presence of a less ‘mature’ glycan matrix environment in the latter region. This finding is supported by a 1.6‐fold increase in the neuroplastic CS‐C (p=0.002) and 1.7‐fold increase in the neuronal attractant CS‐D (p=0.0001) isomers, along with a 39%‐decrease in axonal repulsive CS‐E (p<0.0001), a 22%‐decrease in synapse stabilizing CS‐B/DS (p=0.06), and a 6%‐decrease in the matrix maturing CS‐A (p=0.02) isomers. The hippocampus also exhibited a 51%‐decrease in the nonsulfated CS‐O (p=0.0001) isomer compared to the adjacent cortex, with the resultant hypersulfation of hippocampal CS/DS‐GAGs (p=0.0001) predicted to increase binding of positively charged extracellular growth factors. These differences in CS/DS‐GAGs between brain regions suggest that whereas the cortex provides a matured matrix environment capable of supporting newly formed circuitry, hippocampal CS/DS‐GAGs retain a developmental sulfation patterning that allows for additional neuronal migration, axon growth, and synapse formation. With this background, we then tested whether 3rd trimester congenital ZIKV infection (fetal d120‐d124) in M. nemestrina influences offspring CS/DS‐GAG sulfation patterns 21d later. We found that whereas no change was observed in the cortex, offspring exposed to congenital ZIKV exhibited a 33%‐decrease in CS‐D (p=0.01) and a 1.5x‐increase in CS‐O (p=0.03) in the hippocampus. This ZIKV‐driven reduction of the axonal attractant CS‐D can be predicted to limit hippocampal neurocircuit formation, potentially exacerbated by reduced retention of growth factors resulting from the increase in nonsulfated CS‐O, which is consistent with previous evidence of reduced hippocampal neurocircuit formation after maternal ZIKV infection. Overall, these results imply that maternal ZIKV infection during late‐stage fetal neurodevelopment 1) targets the immature hippocampal CS/DS‐GAGs over the matured cortex, 2) identifies recoding of CS/DS‐GAGs as a novel target for ZIKV infection, and 3) offers a novel and plausible mechanism to explain the deleterious impact of maternal ZIKV on offspring development

Optic Tract as an Upper Limit in Amygdalectomy: Microsurgical Study.

In surgeries involving resection of the amygdala, despite clear relations established with the medial, lateral, anterior, posterior, and inferior segments, the upper limit remains controversial. The optic tract (OT) has been anatomically considered as a good landmark immediately inferior to the striatopallidal region. This anatomic structure has barely been explored by microsurgical study, generating uncertainty about the exact relationship with the surrounding structures. To describe the OT in its entire length through microsurgical study, showing its superior, inferior, medial, and lateral relationships and highlighting its value as a landmark in superior amygdala resection. Microsurgical anatomic dissection of the OT, from its origin in the chiasm to the lateral geniculate nucleus was performed in 8 alcohol-fixed human hemispheres, showing its different segments and relations. Photographs were taken from different angles to facilitate surgical orientation. We performed a dissection of the OT, showing its position relative to caudate and hippocampal formations. We exposed the structures related to the OT superiorly (striatopallidal region and superior caudate fasciculus), inferiorly (head of the hippocampus, amygdala, anterior choroidal artery, perforating artery branch of the anterior choroidal artery, terminal stria, and basal vein), medially (internal capsule and midbrain), and laterally (temporal stem [uncinate and inferior fronto-occipital fascicle], anterior perforated substance, and superior caudate fasciculus). To date, there is a paucity of articles describing the anatomy of the OT from a neurosurgery perspective. In this study, we describe the microsurgical anatomic path of the OT, as a reliable upper limit landmark for amygdala resection.

Multimodal, Multiscale Insights into Hippocampal Seizures Enabled by Transparent, Graphene-Based Microelectrode Arrays.

Hippocampal seizures are a defining feature of mesial temporal lobe epilepsy (MTLE). Area CA1 of the hippocampus is commonly implicated in the generation of seizures, which may occur because of the activity of endogenous cell populations or of inputs from other regions within the hippocampal formation. Simultaneously observing activity at the cellular and network scales in vivo remains challenging. Here, we present a novel technology for simultaneous electrophysiology and multicellular calcium imaging of CA1 pyramidal cells (PCs) in mice enabled by a transparent graphene-based microelectrode array (Gr MEA). We examine PC firing at seizure onset, oscillatory coupling, and the dynamics of the seizure traveling wave as seizures evolve. Finally, we couple features derived from both modalities to predict the speed of the traveling wave using bootstrap aggregated regression trees. Analysis of the most important features in the regression trees suggests a transition among states in the evolution of hippocampal seizures.