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15 pages, 2630 KiB

Open AccessArticle

Reducing FKBP51 Expression in the Ventral Hippocampus Decreases Auditory Fear Conditioning in Male Rats

by Nashaly Irizarry-Méndez, Marangelie Criado-Marrero, Anixa Hernandez, Maria Colón and James T. Porter

Int. J. Mol. Sci. 2024, 25(13), 7097; https://doi.org/10.3390/ijms25137097 - 28 Jun 2024

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Abstract

Fear conditioning evokes a physiologic release of glucocorticoids that assists learning. As a cochaperone in the glucocorticoid receptor complex, FKBP51 modulates stress-induced glucocorticoid signaling and may influence conditioned fear responses. This study combines molecular and behavioral approaches to examine whether locally reducing FKBP51 [...] Read more.

Fear conditioning evokes a physiologic release of glucocorticoids that assists learning. As a cochaperone in the glucocorticoid receptor complex, FKBP51 modulates stress-induced glucocorticoid signaling and may influence conditioned fear responses. This study combines molecular and behavioral approaches to examine whether locally reducing FKBP51 expression in the ventral hippocampus is sufficient to affect fear-related behaviors. We hypothesized that reducing FKBP51 expression in the VH would increase glucocorticoid signaling to alter auditory fear conditioning. Adult male rats were injected with an adeno-associated virus (AAV) vector expressing short hairpin – RNAs (shRNA) targeting FKBP5 into the ventral hippocampus to reduce FKBP5 levels or a control AAV. Infusion of FKBP5-shRNA into the ventral hippocampus decreased auditory fear acquisition and recall. Although animals injected with FKBP5-shRNA showed less freezing during extinction recall, the difference was due to a reduced fear recall rather than improved extinction. Reducing ventral hippocampus FKBP51 did not affect exploratory behavior in either the open field test or the elevated zero maze test but did increase passive behavior in the forced swim test, suggesting that the reduction in auditory fear recall was not due to more active responses to acute stress. Furthermore, lower ventral hippocampus FKBP51 levels did not alter corticosterone release in response to restraint stress, suggesting that the reduced fear recall was not due to lower corticosterone release. Our findings suggest FKBP51 in the ventral hippocampus plays a selective role in modulating fear-learning processes and passive behavioral responses to acute stress rather than hypothalamic-pituitary-adrenal axis reactivity or exploratory responses. Full article

(This article belongs to the Special Issue Focus on Hippocampus Biology: From Neurophysiology to Dysfunctions)

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24 pages, 2057 KiB

Open AccessArticle

by Giota Tsotsokou, Athina Miliou, George Trompoukis, Leonidas J. Leontiadis and Costas Papatheodoropoulos

Int. J. Mol. Sci. 2024, 25(13), 6975; https://doi.org/10.3390/ijms25136975 - 26 Jun 2024

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Abstract

Fragile X syndrome (FXS) is an intellectual developmental disorder characterized, inter alia, by deficits in the short-term processing of neural information, such as sensory processing and working memory. The primary cause of FXS is the loss of fragile X messenger ribonucleoprotein (FMRP), which [...] Read more.

Fragile X syndrome (FXS) is an intellectual developmental disorder characterized, inter alia, by deficits in the short-term processing of neural information, such as sensory processing and working memory. The primary cause of FXS is the loss of fragile X messenger ribonucleoprotein (FMRP), which is profoundly involved in synaptic function and plasticity. Short-term synaptic plasticity (STSP) may play important roles in functions that are affected by FXS. Recent evidence points to the crucial involvement of the presynaptic calcium sensor synaptotagmin-7 (Syt-7) in STSP. However, how the loss of FMRP affects STSP and Syt-7 have been insufficiently studied. Furthermore, males and females are affected differently by FXS, but the underlying mechanisms remain elusive. The aim of the present study was to investigate possible changes in STSP and the expression of Syt-7 in the dorsal (DH) and ventral (VH) hippocampus of adult males and females in a Fmr1-knockout (KO) rat model of FXS. We found that the paired-pulse ratio (PPR) and frequency facilitation/depression (FF/D), two forms of STSP, as well as the expression of Syt-7, are normal in adult KO males, but the PPR is increased in the ventral hippocampus of KO females (6.4 ± 3.7 vs. 18.3 ± 4.2 at 25 ms in wild type (WT) and KO, respectively). Furthermore, we found no gender-related differences, but did find robust region-dependent difference in the STSP (e.g., the PPR at 50 ms: 50.0 ± 5.5 vs. 17.6 ± 2.9 in DH and VH of WT male rats; 53.1 ± 3.6 vs. 19.3 ± 4.6 in DH and VH of WT female rats; 48.1 ± 2.3 vs. 19.1 ± 3.3 in DH and VH of KO male rats; and 51.2 ± 3.3 vs. 24.7 ± 4.3 in DH and VH of KO female rats). AMPA receptors are similarly expressed in the two hippocampal segments of the two genotypes and in both genders. Also, basal excitatory synaptic transmission is higher in males compared to females. Interestingly, we found more than a twofold higher level of Syt-7, not synaptotagmin-1, in the dorsal compared to the ventral hippocampus in the males of both genotypes (0.43 ± 0.1 vs. 0.16 ± 0.02 in DH and VH of WT male rats, and 0.6 ± 0.13 vs. 0.23 ± 0.04 in DH and VH of KO male rats) and in the WT females (0.97 ± 0.23 vs. 0.31 ± 0.09 in DH and VH). These results point to the susceptibility of the female ventral hippocampus to FMRP loss. Importantly, the different levels of Syt-7, which parallel the higher score of the dorsal vs. ventral hippocampus on synaptic facilitation, suggest that Syt-7 may play a pivotal role in defining the striking differences in STSP along the long axis of the hippocampus. Full article

(This article belongs to the Special Issue Focus on Hippocampus Biology: From Neurophysiology to Dysfunctions)

12 pages, 1036 KiB

Open AccessArticle

A Reduction in the Readily Releasable Vesicle Pool Impairs GABAergic Inhibition in the Hippocampus after Blood–Brain Barrier Dysfunction

by Kristina Lippmann

Int. J. Mol. Sci. 2024, 25(13), 6862; https://doi.org/10.3390/ijms25136862 - 22 Jun 2024

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Abstract

Major burdens for patients suffering from stroke are cognitive co-morbidities and epileptogenesis. Neural network disinhibition and deficient inhibitive pulses for fast network activities may result from impaired presynaptic release of the inhibitory neurotransmitter GABA. To test this hypothesis, a cortical photothrombotic stroke was [...] Read more.

Major burdens for patients suffering from stroke are cognitive co-morbidities and epileptogenesis. Neural network disinhibition and deficient inhibitive pulses for fast network activities may result from impaired presynaptic release of the inhibitory neurotransmitter GABA. To test this hypothesis, a cortical photothrombotic stroke was induced in Sprague Dawley rats, and inhibitory currents were recorded seven days later in the peri-infarct blood–brain barrier disrupted (BBBd) hippocampus via patch-clamp electrophysiology in CA1 pyramidal cells (PC). Miniature inhibitory postsynaptic current (mIPSC) frequency was reduced to about half, and mIPSCs decayed faster in the BBBd hippocampus. Furthermore, the paired-pulse ratio of evoked GABA release was increased at 100 Hz, and train stimulations with 100 Hz revealed that the readily releasable pool (RRP), usually assumed to correspond to the number of tightly docked presynaptic vesicles, is reduced by about half in the BBBd hippocampus. These pathophysiologic changes are likely to contribute significantly to disturbed fast oscillatory activity, like cognition-associated gamma oscillations or sharp wave ripples and epileptogenesis in the BBBd hippocampus. Full article

(This article belongs to the Special Issue Focus on Hippocampus Biology: From Neurophysiology to Dysfunctions)

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19 pages, 3447 KiB

Open AccessArticle

A Continuous Attractor Model with Realistic Neural and Synaptic Properties Quantitatively Reproduces Grid Cell Physiology

by Nate M. Sutton, Blanca E. Gutiérrez-Guzmán, Holger Dannenberg and Giorgio A. Ascoli

Int. J. Mol. Sci. 2024, 25(11), 6059; https://doi.org/10.3390/ijms25116059 - 31 May 2024

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Abstract

Computational simulations with data-driven physiological detail can foster a deeper understanding of the neural mechanisms involved in cognition. Here, we utilize the wealth of cellular properties from Hippocampome.org to study neural mechanisms of spatial coding with a spiking continuous attractor network model of [...] Read more.

Computational simulations with data-driven physiological detail can foster a deeper understanding of the neural mechanisms involved in cognition. Here, we utilize the wealth of cellular properties from Hippocampome.org to study neural mechanisms of spatial coding with a spiking continuous attractor network model of medial entorhinal cortex circuit activity. The primary goal is to investigate if adding such realistic constraints could produce firing patterns similar to those measured in real neurons. Biological characteristics included in the work are excitability, connectivity, and synaptic signaling of neuron types defined primarily by their axonal and dendritic morphologies. We investigate the spiking dynamics in specific neuron types and the synaptic activities between groups of neurons. Modeling the rodent hippocampal formation keeps the simulations to a computationally reasonable scale while also anchoring the parameters and results to experimental measurements. Our model generates grid cell activity that well matches the spacing, size, and firing rates of grid fields recorded in live behaving animals from both published datasets and new experiments performed for this study. Our simulations also recreate different scales of those properties, e.g., small and large, as found along the dorsoventral axis of the medial entorhinal cortex. Computational exploration of neuronal and synaptic model parameters reveals that a broad range of neural properties produce grid fields in the simulation. These results demonstrate that the continuous attractor network model of grid cells is compatible with a spiking neural network implementation sourcing data-driven biophysical and anatomical parameters from Hippocampome.org. The software (version 1.0) is released as open source to enable broad community reuse and encourage novel applications. Full article

(This article belongs to the Special Issue Focus on Hippocampus Biology: From Neurophysiology to Dysfunctions)

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26 pages, 17175 KiB

Open AccessArticle

High-Caloric Diets in Adolescence Impair Specific GABAergic Subpopulations, Neurogenesis, and Alter Astrocyte Morphology

by Bárbara Mota, Ana Rita Brás, Leonardo Araújo-Andrade, Ana Silva, Pedro A. Pereira, M. Dulce Madeira and Armando Cardoso

Int. J. Mol. Sci. 2024, 25(10), 5524; https://doi.org/10.3390/ijms25105524 - 18 May 2024

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Abstract

We compared the effects of two different high-caloric diets administered to 4-week-old rats for 12 weeks: a diet rich in sugar (30% sucrose) and a cafeteria diet rich in sugar and high-fat foods. We focused on the hippocampus, particularly on the gamma-aminobutyric acid [...] Read more.

We compared the effects of two different high-caloric diets administered to 4-week-old rats for 12 weeks: a diet rich in sugar (30% sucrose) and a cafeteria diet rich in sugar and high-fat foods. We focused on the hippocampus, particularly on the gamma-aminobutyric acid (GABA)ergic system, including the Ca²⁺-binding proteins parvalbumin (PV), calretinin (CR), calbindin (CB), and the neuropeptides somatostatin (SST) and neuropeptide Y (NPY). We also analyzed the density of cholinergic varicosities, brain-derived neurotrophic factor (BDNF), reelin (RELN), and cyclin-dependent kinase-5 (CDK-5) mRNA levels, and glial fibrillary acidic protein (GFAP) expression. The cafeteria diet reduced PV-positive neurons in the granular layer, hilus, and CA1, as well as NPY-positive neurons in the hilus, without altering other GABAergic populations or overall GABA levels. The high-sugar diet induced a decrease in the number of PV-positive cells in CA3 and an increase in CB-positive cells in the hilus and CA1. No alterations were observed in the cholinergic varicosities. The cafeteria diet also reduced the relative mRNA expression of RELN without significant changes in BDNF and CDK5 levels. The cafeteria diet increased the number but reduced the length of the astrocyte processes. These data highlight the significance of determining the mechanisms mediating the observed effects of these diets and imply that the cognitive impairments previously found might be related to both the neuroinflammation process and the reduction in PV, NPY, and RELN expression in the hippocampal formation. Full article

(This article belongs to the Special Issue Focus on Hippocampus Biology: From Neurophysiology to Dysfunctions)

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16 pages, 16571 KiB

Open AccessArticle

Complex Hippocampal Response to Thermal Skin Injury and Protocols with Hyperbaric Oxygen Therapy and Filipendula ulmaria Extract in Rats

by Bojana Krstic, Dragica Selakovic, Nemanja Jovicic, Milos Krstic, Jelena S. Katanic Stankovic, Sara Rosic, Dragan Milovanovic and Gvozden Rosic

Int. J. Mol. Sci. 2024, 25(5), 3033; https://doi.org/10.3390/ijms25053033 - 6 Mar 2024

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Abstract

The aim of this study was to evaluate the alterations of the hippocampal function that may be related to anxiogenic response to thermal skin injury, including the morpho-functional alterations, and the effects of hyperbaric oxygen (HBO) and Filipendula ulmaria (FU) extract in the [...] Read more.

The aim of this study was to evaluate the alterations of the hippocampal function that may be related to anxiogenic response to thermal skin injury, including the morpho-functional alterations, and the effects of hyperbaric oxygen (HBO) and Filipendula ulmaria (FU) extract in the treatment of anxiety-like behavior that coincides with thermal skin injury. A rat thermal skin injury experimental model was performed on 2-month-old male Wistar albino rats. The evaluated therapeutic protocols included HBO and/or antioxidant supplementation. HBO was applied for 7 days in the hyperbaric chamber (100% O₂, 2.5 ATA, 60 min). Oral administration of FU extract (final concentration of 100 mg/kg b.w.) to achieve antioxidant supplementation was also applied for 7 days. Anxiety level was estimated in the open field and elevated plus-maze test, which was followed by anesthesia, sacrifice, and collection of hippocampal tissue samples. HBO treatment and FU supplementation significantly abolished anxiogenic response to thermal skin injury. This beneficial effect was accompanied by the reduction in hippocampal pro-inflammatory and pro-apoptotic indicators, and enhanced BDNF and GABA-ARα2S gene expression, previously observed in untreated burns. The hippocampal relative gene expression of melatonin receptors and NPY positively responded to the applied protocols, in the same manner as µ and δ opioid receptors, while the opposite response was observed for κ receptors. The results of this study provide some confirmations that adjuvant strategies, such as HBO and antioxidant supplementation, may be simultaneously applied in the treatment of the anxiety-like behavior that coincides with thermal skin injury. Full article

(This article belongs to the Special Issue Focus on Hippocampus Biology: From Neurophysiology to Dysfunctions)

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16 pages, 4629 KiB

Open AccessArticle

Increased Dentate Gyrus Excitability in the Intrahippocampal Kainic Acid Mouse Model for Temporal Lobe Epilepsy

by Marijke Vergaelen, Simona Manzella, Kristl Vonck, Erine Craey, Jeroen Spanoghe, Mathieu Sprengers, Evelien Carrette, Wytse Jan Wadman, Jean Delbeke, Paul Boon, Lars Emil Larsen and Robrecht Raedt

Int. J. Mol. Sci. 2024, 25(1), 660; https://doi.org/10.3390/ijms25010660 - 4 Jan 2024

Cited by 1 | Viewed by 1511

Abstract

The intrahippocampal kainic acid (IHKA) mouse model is an extensively used in vivo model to investigate the pathophysiology of mesial temporal lobe epilepsy (mTLE) and to develop novel therapies for drug-resistant epilepsy. It is characterized by profound hippocampal sclerosis and spontaneously occurring seizures [...] Read more.

The intrahippocampal kainic acid (IHKA) mouse model is an extensively used in vivo model to investigate the pathophysiology of mesial temporal lobe epilepsy (mTLE) and to develop novel therapies for drug-resistant epilepsy. It is characterized by profound hippocampal sclerosis and spontaneously occurring seizures with a major role for the injected damaged hippocampus, but little is known about the excitability of specific subregions. The purpose of this study was to electrophysiologically characterize the excitability of hippocampal subregions in the chronic phase of the induced epilepsy in the IHKA mouse model. We recorded field postsynaptic potentials (fPSPs) after electrical stimulation in the CA1 region and in the dentate gyrus (DG) of hippocampal slices of IHKA and healthy mice using a multielectrode array (MEA). In the DG, a significantly steeper fPSP slope was found, reflecting higher synaptic strength. Population spikes were more prevalent with a larger spatial distribution in the IHKA group, reflecting a higher degree of granule cell output. Only minor differences were found in the CA1 region. These results point to increased neuronal excitability in the DG but not in the CA1 region of the hippocampus of IHKA mice. This method, in which the excitability of hippocampal slices from IHKA mice is investigated using a MEA, can now be further explored as a potential new model to screen for new interventions that can restore DG function and potentially lead to novel therapies for mTLE. Full article

(This article belongs to the Special Issue Focus on Hippocampus Biology: From Neurophysiology to Dysfunctions)

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11 pages, 2868 KiB

Open AccessArticle

The Effects of Stress on Hippocampal Neurogenesis and Behavior in the Absence of Lipocalin-2

by Ana Catarina Ferreira and Fernanda Marques

Int. J. Mol. Sci. 2023, 24(21), 15537; https://doi.org/10.3390/ijms242115537 - 24 Oct 2023

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Abstract

Lipocalin-2 (LCN2) is an acute phase protein able to bind iron when complexed with bacterial siderophores. The recent identification of a mammalian siderophore also suggested a physiological role for LCN2 in the regulation of iron levels and redox state. In the central nervous [...] Read more.

Lipocalin-2 (LCN2) is an acute phase protein able to bind iron when complexed with bacterial siderophores. The recent identification of a mammalian siderophore also suggested a physiological role for LCN2 in the regulation of iron levels and redox state. In the central nervous system, the deletion of LCN2 induces deficits in neural stem cells proliferation and commitment, with an impact on the hippocampal-dependent contextual fear discriminative task. Additionally, stress is a well-known regulator of cell genesis and is known to decrease adult hippocampal cell proliferation and neurogenesis. Although voluntary running, another well-known regulator of neurogenesis, is sufficient to rescue the defective hippocampal neurogenesis and behavior in LCN2-null mice by promoting stem cells’ cell cycle progression and maturation, the relevance of LCN2-regulated hippocampal neurogenesis in response to stress has never been explored. Here, we show a lack of response by LCN2-null mice to the effects of chronic stress exposure at the cellular and behavioral levels. Together, these findings implicate LCN2 as a relevant mediator of neuronal plasticity and brain function in the adult mammalian brain. Full article

(This article belongs to the Special Issue Focus on Hippocampus Biology: From Neurophysiology to Dysfunctions)

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20 pages, 2545 KiB

Open AccessArticle

Dorsal–Ventral Gradient of Activin Regulates Strength of GABAergic Inhibition along Longitudinal Axis of Mouse Hippocampus in an Activity-Dependent Fashion

by Maria Jesus Valero-Aracama, Fang Zheng and Christian Alzheimer

Int. J. Mol. Sci. 2023, 24(17), 13145; https://doi.org/10.3390/ijms241713145 - 24 Aug 2023

Cited by 2 | Viewed by 757

Abstract

The functional and neurophysiological distinction between the dorsal and ventral hippocampus affects also GABAergic inhibition. In line with this notion, ventral CA1 pyramidal cells displayed a more dynamic and effective response to inhibitory input compared to their dorsal counterparts. We posit that this [...] Read more.

The functional and neurophysiological distinction between the dorsal and ventral hippocampus affects also GABAergic inhibition. In line with this notion, ventral CA1 pyramidal cells displayed a more dynamic and effective response to inhibitory input compared to their dorsal counterparts. We posit that this difference is effected by the dorsal–ventral gradient of activin A, a member of the transforming growth factor-β family, which is increasingly recognized for its modulatory role in brain regions involved in cognitive functions and affective behavior. Lending credence to this hypothesis, we found that in slices from transgenic mice expressing a dominant-negative mutant of activin receptor IB (dnActRIB), inhibitory transmission was enhanced only in CA1 neurons of the dorsal hippocampus, where the basal activin A level is much higher than in the ventral hippocampus. We next asked how a rise in endogenous activin A would affect GABAergic inhibition along the longitudinal axis of the hippocampus. We performed ex vivo recordings in wild-type and dnActRIB mice after overnight exposure to an enriched environment (EE), which engenders a robust increase in activin A levels in both dorsal and ventral hippocampi. Compared to control mice from standard cages, the behaviorally induced surge in activin A produced a decline in ventral inhibition, an effect that was absent in slices from dnActRIB mice. Underscoring the essential role of activin in the EE-associated modulation of ventral inhibition, this effect was mimicked by acute application of recombinant activin A in control slices. In summary, both genetic and behavioral manipulations of activin receptor signaling affected the dorsal–ventral difference in synaptic inhibition, suggesting that activin A regulates the strength of GABAergic inhibition in a region-specific fashion. Full article

(This article belongs to the Special Issue Focus on Hippocampus Biology: From Neurophysiology to Dysfunctions)

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Review

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24 pages, 1052 KiB

Open AccessReview

Glucose Transport and Utilization in the Hippocampus: From Neurophysiology to Diabetes-Related Development of Dementia

by Caio Yogi Yonamine, Maria Luiza Estimo Michalani, Rafael Junges Moreira and Ubiratan Fabres Machado

Int. J. Mol. Sci. 2023, 24(22), 16480; https://doi.org/10.3390/ijms242216480 - 18 Nov 2023

Cited by 1 | Viewed by 2069

Abstract

The association of diabetes with cognitive dysfunction has at least 60 years of history, which started with the observation that children with type 1 diabetes mellitus (T1D), who had recurrent episodes of hypoglycemia and consequently low glucose supply to the brain, showed a [...] Read more.

The association of diabetes with cognitive dysfunction has at least 60 years of history, which started with the observation that children with type 1 diabetes mellitus (T1D), who had recurrent episodes of hypoglycemia and consequently low glucose supply to the brain, showed a deficit of cognitive capacity. Later, the growing incidence of type 2 diabetes mellitus (T2D) and dementia in aged populations revealed their high association, in which a reduced neuronal glucose supply has also been considered as a key mechanism, despite hyperglycemia. Here, we discuss the role of glucose in neuronal functioning/preservation, and how peripheral blood glucose accesses the neuronal intracellular compartment, including the exquisite glucose flux across the blood–brain barrier (BBB) and the complex network of glucose transporters, in dementia-related areas such as the hippocampus. In addition, insulin resistance-induced abnormalities in the hippocampus of obese/T2D patients, such as inflammatory stress, oxidative stress, and mitochondrial stress, increased generation of advanced glycated end products and BBB dysfunction, as well as their association with dementia/Alzheimer’s disease, are addressed. Finally, we discuss how these abnormalities are accompained by the reduction in the expression and translocation of the high capacity insulin-sensitive glucose transporter GLUT4 in hippocampal neurons, which leads to neurocytoglycopenia and eventually to cognitive dysfunction. This knowledge should further encourage investigations into the beneficial effects of promising therapeutic approaches which could improve central insulin sensitivity and GLUT4 expression, to fight diabetes-related cognitive dysfunctions. Full article

(This article belongs to the Special Issue Focus on Hippocampus Biology: From Neurophysiology to Dysfunctions)

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