Hippocampal CA1 Subfield Research Articles

Automated volumetry of hippocampal subfields in temporal lobe epilepsy

IntroductionHippocampal sclerosis is the most frequent pathological substrate in drug resistant temporal lobe epilepsy (TLE). Recently 4 types of hippocampal sclerosis (HS) have been defined in a task force by the International League Against Epilepsy (ILAE), based on patterns of cell loss in specific hippocampal subfields. Type 1 HS is most frequent and has the most favorable outcome after epilepsy surgery. We hypothesized that volume loss in specific hippocampal subfields determined by automated volumetry of high resolution MRI would correspond to cell loss in histological reports. Material and MethodsIn a group of well characterized patients with drug resistant TLE (N = 26 patients, 14 with right-sided focus, 12 with left-sided focus) volumes of the right and left hippocampus and the hippocampal subfields CA1, CA2 + 3, CA4 and dentate gyrus (DG) were estimated automatically using FreeSurfer version 6.0 from high-resolution cerebral MRI and compared to a large group of healthy controls (N = 121). HS subtype classification was attempted based on histological reports. ResultsVolumes of the whole hippocampus and all investigated hippocampal subfields (CA1, CA2 + 3, CA4 and DG) were significantly lower on the ipsilateral compared the contralateral side (p < 0.001) and compared to the healthy controls (p < 0.001). Conversely, whole hippocampal and hippocampal subfield volumes were not significantly different from healthy control values on the contralateral side.In 12 of 20 patients the pattern of hippocampal volume loss in specific subfields was in accordance with HS types from histology. The highest overlap between automated MRI and histology was achieved for type 1 HS (in 10 of 12 cases). ConclusionThe automated volumetry of hippocampal subfields, based on high resolution MRI, may have the potential to predict the pattern of cell loss in hippocampal sclerosis before operation.

A neurostructural biomarker of dissociative amnesia: a hippocampal study in dissociative identity disorder.

Little is known about the neural correlates of dissociative amnesia, a transdiagnostic symptom mostly present in the dissociative disorders and core characteristic of dissociative identity disorder (DID). Given the vital role of the hippocampus in memory, a prime candidate for investigation is whether total and/or subfield hippocampal volume can serve as biological markers of dissociative amnesia. A total of 75 women, 32 with DID and 43 matched healthy controls (HC), underwent structural magnetic resonance imaging (MRI). Using Freesurfer (version 6.0), volumes were extracted for bilateral global hippocampus, cornu ammonis (CA) 1-4, the granule cell molecular layer of the dentate gyrus (GC-ML-DG), fimbria, hippocampal-amygdaloid transition area (HATA), parasubiculum, presubiculum and subiculum. Analyses of covariance showed volumetric differences between DID and HC. Partial correlations exhibited relationships between the three factors of the dissociative experience scale scores (dissociative amnesia, absorption, depersonalisation/derealisation) and traumatisation measures with hippocampal global and subfield volumes. Hippocampal volumes were found to be smaller in DID as compared with HC in bilateral global hippocampus and bilateral CA1, right CA4, right GC-ML-DG, and left presubiculum. Dissociative amnesia was the only dissociative symptom that correlated uniquely and significantly with reduced bilateral hippocampal CA1 subfield volumes. Regarding traumatisation, only emotional neglect correlated negatively with bilateral global hippocampus, bilateral CA1, CA4 and GC-ML-DG, and right CA3. We propose decreased CA1 volume as a biomarker for dissociative amnesia. We also propose that traumatisation, specifically emotional neglect, is interlinked with dissociative amnesia in having a detrimental effect on hippocampal volume.

Rare CASP6N73T variant associated with hippocampal volume exhibits decreased proteolytic activity, synaptic transmission defect, and neurodegeneration

Caspase-6 (Casp6) is implicated in Alzheimer disease (AD) cognitive impairment and pathology. Hippocampal atrophy is associated with cognitive impairment in AD. Here, a rare functional exonic missense CASP6 single nucleotide polymorphism (SNP), causing the substitution of asparagine with threonine at amino acid 73 in Casp6 (Casp6N73T), was associated with hippocampal subfield CA1 volume preservation. Compared to wild type Casp6 (Casp6WT), recombinant Casp6N73T altered Casp6 proteolysis of natural substrates Lamin A/C and α-Tubulin, but did not alter cleavage of the Ac-VEID-AFC Casp6 peptide substrate. Casp6N73T-transfected HEK293T cells showed elevated Casp6 mRNA levels similar to Casp6WT-transfected cells, but, in contrast to Casp6WT, did not accumulate active Casp6 subunits nor show increased Casp6 enzymatic activity. Electrophysiological and morphological assessments showed that Casp6N73T recombinant protein caused less neurofunctional damage and neurodegeneration in hippocampal CA1 pyramidal neurons than Casp6WT. Lastly, CASP6 mRNA levels were increased in several AD brain regions confirming the implication of Casp6 in AD. These studies suggest that the rare Casp6N73T variant may protect against hippocampal atrophy due to its altered catalysis of natural protein substrates and intracellular instability thus leading to less Casp6-mediated damage to neuronal structure and function.

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer\u2019s disease

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease, characterized by hyperphosphorylated tau, found in individuals with a history of exposure to repetitive head impacts. While the neuropathologic hallmark of CTE is found in the cortex, hippocampal tau has proven to be an important neuropathologic feature to examine the extent of disease severity. However, the hippocampus is also heavily affected in many other tauopathies, such as Alzheimer’s disease (AD). How CTE and AD differentially affect the hippocampus is unclear. Using immunofluorescent analysis, a detailed histologic characterization of 3R and 4R tau isoforms and their differential accumulation in the temporal cortex in CTE and AD was performed. CTE and AD were both observed to contain mixed 3R and 4R tau isoforms, with 4R predominating in mild disease and 3R increasing proportionally as pathological severity increased. CTE demonstrated high levels of tau in hippocampal subfields CA2 and CA3 compared to CA1. There were also low levels of tau in the subiculum compared to CA1 in CTE. In contrast, AD had higher levels of tau in CA1 and subiculum compared to CA2/3. Direct comparison of the tau burden between AD and CTE demonstrated that CTE had higher tau densities in CA4 and CA2/3, while AD had elevated tau in the subiculum. Amyloid beta pathology did not contribute to tau isoform levels. Finally, it was demonstrated that higher levels of 3R tau correlated to more severe extracellular tau (ghost tangles) pathology. These findings suggest that mixed 3R/4R tauopathies begin as 4R predominant then transition to 3R predominant as pathological severity increases and ghost tangles develop. Overall, this work demonstrates that the relative deposition of tau isoforms among hippocampal subfields can aid in differential diagnosis of AD and CTE, and might help improve specificity of biomarkers for in vivo diagnosis.

Selective morphological and volumetric alterations in the hippocampus of children exposed in utero to gestational diabetes mellitus.

Prior epidemiological studies have found that in utero exposure to gestational diabetes mellitus (GDM) is associated with increased risk for neurodevelopmental disorders. However, brain alterations associated with GDM are not known. The hippocampus is pivotal for cognition and emotional regulation. Therefore, we assessed relationships between in utero exposure to GDM and hippocampal morphology and subfield structure during childhood. One hundred seventeen children aged 7–11 years (57% girls, 57% exposed to GDM), born at Kaiser Permanente Southern California, participated in the BrainChild Study. Maternal GDM status was determined from electronic medical records. Children underwent brain magnetic resonance imaging. Freesurfer 6.0 was used to measure hippocampal and individual hippocampal subfield gray matter volume (mm3). Morphological analyses on the hippocampal surface were carried out using shape analysis. GDM‐exposed children exhibited reduced radial thickness in a small, spatially‐restricted portion of the left inferior body of the hippocampus that corresponds to the CA1 subfield. There was a significant interaction between GDM‐exposure and sex on the right hippocampal CA1 subfield. GDM‐exposed boys had reduced right CA1 volume compared to unexposed boys, but this association was no longer significant after controlling for age. No significant group differences were observed in girls. Our results suggest that GDM‐exposure impacts shape of the left hippocampal CA1 subfield in both boys and girls and may reduce volume of right hippocampal CA1 only in boys. These in‐depth findings illuminate the unique properties of the hippocampus impacted by prenatal GDM‐exposure and could have important implications for hippocampal‐related functions.

Short-Term Amygdala Low-Frequency Stimulation Does not Influence Hippocampal Interneuron Changes Observed in the Pilocarpine Model of Epilepsy.

Temporal lobe epilepsy (TLE) is characterized by changes in interneuron numbers in the hippocampus. Deep brain stimulation (DBS) is an emerging tool to treat TLE seizures, although its mechanisms are not fully deciphered. We aimed to depict the effect of amygdala DBS on the density of the most common interneuron types in the CA1 hippocampal subfield in the lithium-pilocarpine model of epilepsy. Status epilepticus was induced in male Wistar rats. Eight weeks later, a stimulation electrode was implanted to the left basolateral amygdala of both pilocarpine-treated (Pilo, n = 14) and age-matched control rats (n = 12). Ten Pilo and 4 control animals received for 10 days 4 daily packages of 50 s 4 Hz regular stimulation trains. At the end of the stimulation period, interneurons were identified by immunolabeling for parvalbumin (PV), neuropeptide Y (NPY), and neuronal nitric oxide synthase (nNOS). Cell density was determined in the CA1 subfield of the hippocampus using confocal microscopy. We found that PV+ cell density was preserved in pilocarpine-treated rats, while the NPY+/nNOS+ cell density decreased significantly. The amygdala DBS did not significantly change the cell density in healthy or in epileptic animals. We conclude that DBS with low frequency applied for 10 days does not influence interneuron cell density changes in the hippocampus of epileptic rats.

Postnatal Fluoxetine Treatment Alters Perineuronal Net Formation and Maintenance in the Hippocampus.

Elevation of serotonin via postnatal fluoxetine (PNFlx) treatment during critical temporal windows is hypothesized to perturb the development of limbic circuits thus establishing a substratum for persistent disruption of mood-related behavior. We examined the impact of PNFlx treatment on the formation and maintenance of perineuronal nets (PNNs), extracellular matrix (ECM) structures that deposit primarily around inhibitory interneurons, and mark the closure of critical period plasticity. PNFlx treatment evoked a significant decline in PNN number, with a robust reduction in PNNs deposited around parvalbumin (PV) interneurons, within the CA1 and CA3 hippocampal subfields at postnatal day (P)21 in Sprague Dawley rat pups. While the reduction in CA1 subfield PNN number was still observed in adulthood, we observed no change in colocalization of PV-positive interneurons with PNNs in the hippocampi of adult PNFlx animals. PNFlx treatment did not alter hippocampal PV, calretinin (CalR), or Reelin-positive neuron numbers in PNFlx animals at P21 or in adulthood. We did observe a small, but significant increase in somatostatin (SST)-positive interneurons in the DG subfield of PNFlx-treated animals in adulthood. This was accompanied by altered GABA-A receptor subunit composition, increased dendritic complexity of apical dendrites of CA1 pyramidal neurons, and enhanced neuronal activation revealed by increased c-Fos-positive cell numbers within hippocampi of PNFlx-treated animals in adulthood. These results indicate that PNFlx treatment alters the formation of PNNs within the hippocampus, raising the possibility of a disruption of excitation-inhibition (E/I) balance within this key limbic brain region.

Hydrogen sulfide protects hippocampal CA1 neurons against lead mediated neuronal damage via reduction oxidative stress in male rats

H2S plays vital roles in modulation brain function. It is associated with antioxidant and anti-inflammatory properties. We assessed the H2S impact on spatial learning and memory deficit and cell death due to lead exposure, and probable mechanisms of action.The 36 male Wistar rats that (200−220 g), were in random assigned to 3 groups, control group (12 rats), lead acetate group (12 rats), and lead acetate +H2S groups (NaHS as a H2S donor; 5/6 mg/kg; 12 rats). Administration of lead to rats was performed through acute lead poisoning (25 mg/kg of lead acetate, IP through 3 days). Using male Morris water maze, their spatial learning and memory function were measured. We carried out ELISA method to calculate TNF-α and antioxidant enzymes level. Immunohistochemical staining was applied for evaluating the caspase-3 expression levels. Treatment with H2S improved learning and memory impairment in Pb-exposed rats (P<0.05). H2S treatment suppressed Pb-related apoptosis in the hippocampal CA1 subfield (P<0.01). Also, the TNF-α over-expression in the CA1 region of hippocampus due to lead exposure showed a significant reduction (P<0.05) after administrating H2S. Simultaneously, H2S treatment reduced the MDA levels, enhanced SOD, GSH level than the Pb-exposed group in hippocampus (P<0.05). H2S was able to significantly improve Pb-related spatial learning and memory deficit, and neuronal cell death in the CA1 region of hippocampus in the male rats at least partly by reducing oxidative stress and TNF

Alzheimer’s disease‐related necroptotic pathology: An exclusive presence of the necrosome in granulovacuolar degeneration inclusions in human and transgenic mouse brains

AbstractBackgroundAlzheimer’s disease (AD) is characterized by pathological processes such as β‐amyloid (Aβ) plaques, neurofibrillary tangles (NFT), cytoplasmic granulovacuolar degeneration (GVD) lesions and neuronal loss that underpin cognitiveand behavioral alterations. Necroptosis, a programmed form of cell death defined by the assembly of the necrosome complex composed of phosphorylated proteins (pRIPK1, pRIPK3 and pMLKL), has recently been shown to be involved in AD.MethodTo determine the neuropathological characteristics and distribution pattern of the necrosome components, we performed a comprehensive immunohistochemical analysis of brains of AD, pathologically defined preclinical AD and non‐AD control cases. A similar analysis was carried out to investigate necroptosis‐related proteins in transgenic mouse models of Aβ and Tau pathology.ResultsWe identified all three activated necrosome components (pRIPK1, pRIPK3 and pMLKL) in GVD inclusionswithin neurons of the hippocampal subfields CA1, CA2/3, CA4, dentate gyrus, subiculum, entorhinal cortex, temporal cortex, hypothalamus, amygdala and frontal cortex of symptomatic and preclinical AD patients. The three necrosome proteins colocalized with standard GVD markers, such as pTDP‐43 and CK1δ, and similarly to these markers detected GVD lesions. Necrosome‐associated GVD neurons inversely correlated with neuronal density in the early affected hippocampus and in the late affected frontal cortex. Necroptosis‐specific GVD lesions showed strong positive associations with AD‐defining parameters, showing the strongest correlation and partial colocalization with Tau pathology. Moreover, we analyzed brain tissues of transgenic mice carrying mutated APP, Tau or both transgenes. We found morphologically comparable GVD lesions positive for the necroptosis components in the subiculum, hippocampus and entorhinal cortex of 12‐month‐old APP23xTAU58 mice. We confirmed mouse necrosome‐positive GVD inclusions by CK1δ immunoreactivity.ConclusionThe presence of the necrosome in GVD inclusions points to a specific form of necroptosis in AD that can be modelled in APPxTAU transgenic mice, possibly indicating Tau and/or Aβ as drivers of this pathology. Necrosome‐positive GVD granules represent a potential protective system sequestering the necrosome complex, which could interfere with or delay necroptosis‐related neuronal death.

Topographic Organization of Correlation Along the Longitudinal and Transverse Axes in Rat Hippocampal CA3 Due to Excitatory Afferents.

The topographic organization of afferents to the hippocampal CA3 subfield are well-studied, but their role in influencing the spatiotemporal dynamics of population activity is not understood. Using a large-scale, computational neuronal network model of the entorhinal-dentate-CA3 system, the effects of the perforant path, mossy fibers, and associational system on the propagation and transformation of network spiking patterns were investigated. A correlation map was constructed to characterize the spatial structure and temporal evolution of pairwise correlations which underlie the emergent patterns found in the population activity. The topographic organization of the associational system gave rise to changes in the spatial correlation structure along the longitudinal and transverse axes of the CA3. The resulting gradients may provide a basis for the known functional organization observed in hippocampus.

P53 upregulated mediator of apoptosis (Puma) deficiency increases survival of adult neural stem cells generated physiologically in the hippocampus, but does not protect stem cells generated in surplus after an excitotoxic lesion.

Neurogenesis occurs in the mammalian brain throughout adulthood and increases in response to metabolic, toxic or traumatic insults. To remove potentially superfluous or unwanted neural stem cells/neuronal progenitors, their rate of proliferation and differentiation is fine-tuned against their rate of apoptosis. Apoptosis requires the transcriptional and posttranslational activation of Bcl-2-homolgy domain 3 (BH3)-only proteins. Previously, we demonstrated that the BH3-only protein p53-upregulated mediator of apoptosis (Puma) controls the physiological rate of apoptosis of neural precursor cells in the adult mouse hippocampus. Puma's role in controlling a lesion-induced increase in neural stem cells is currently not known. We employed a model of local, N-methyl-D-asparte (NMDA)-induced excitotoxic injury to the CA1 hippocampal subfield and immunofluorescence labelling to produce increased neural stem cell proliferation/ neurogenesis in the dentate gyrus at two survival times following the excitotoxic lesion. Deletion of puma failed to rescue any NMDA-induced increase in adult born cells as assessed by BrdU or Doublecortin labelling in the long-term. No difference in the proportion of BrdU/NeuN-positive cells comparing the different genotypes and treatments suggested that the phenotypic fate of the cells was preserved regardless of the genotype and the treatment. While neurogenesis is up-regulated in puma-deficient animals following NMDA-induced excitotoxicity to the hippocampal CA1 subfield, puma deficiency could not protect this surplus of newly generated cells from apoptotic cell death.

Chronic central modulation of LPA/LPA receptors-signaling pathway in the mouse brain regulates cognition, emotion, and hippocampal neurogenesis

Several studies have demonstrated that lysophosphatidic acid (LPA) acts through its LPA receptors in multiple biological and behavioral processes, including adult hippocampal neurogenesis, hippocampal-dependent memory, and emotional regulation. However, analyses of the effects have typically involved acute treatments, and there is no information available regarding the effect of the chronic pharmacological modulation of the LPA/LPA receptors-signaling pathway. Thus, we analyzed the effect of the chronic (21 days) and continuous intracerebroventricular (ICV) infusion of C18:1 LPA and the LPA1-3 receptor antagonist Ki16425 in behavior and adult hippocampal neurogenesis. Twenty-one days after continuous ICV infusions, mouse behaviors in the open field test, Y-maze test and forced swimming test were assessed. In addition, the hippocampus was examined for c-Fos expression and α-CaMKII and phospho-α-CaMKII levels.The current study demonstrates that chronic C18:1 LPA produced antidepressant effects, improved spatial working memory, and enhanced adult hippocampal neurogenesis. In contrast, chronic LPA1-3 receptor antagonism disrupted exploratory activity and spatial working memory, induced anxiety and depression-like behaviors and produced an impairment of hippocampal neurogenesis. While these effects were accompanied by an increase in neuronal activation in the DG of C18:1 LPA-treated mice, Ki16425-treated mice showed reduced neuronal activation in CA3 and CA1 hippocampal subfields. Treatment with the antagonist also induced an imbalance in the expression of basal/activated α-CaMKII protein forms.These outcomes indicate that the chronic central modulation of the LPA receptors-signaling pathway in the brain regulates cognition and emotion, likely comprising hippocampal-dependent mechanisms. The use of pharmacological modulation of this pathway in the brain may potentially be targeted for the treatment of several neuropsychiatric conditions.

Prolactin neuroprotective action against excitotoxic insult in the hippocampus of male mice

Prolactin (PRL) is known to exert neuroprotective effects against excitotoxic damage in the hippocampus of female rats, both in vitro and in vivo. It is still unknown whether this effect can be seen in the male hippocampus and intracellular signaling mediating such action. To assess this, adult male CD-1 mice were subjected to excitotoxic damage with kainic acid (KA; i.c.v.), after a) no manipulation (control group), b) treatment with saline, and c) treatment with PRL (8 μg of PRL/100 μl of saline s.c.). Treatments consisted of one daily injection of the mentioned dosage for seven consecutive days until the day of the excitotoxic lesion. Neurodegeneration (Fluoro-Jade C), neuronal survival (NeuN) and astrogliosis (GFAP) markers were identified with immunohistochemistry in the CA1, CA3 and CA4 areas of the dorsal hippocampus, as well as PRL-related protein levels by Western blot in the whole hippocampus 48 h after excitotoxicity. Anatomical measurements revealed a preferential protective effect of PRL against excitotoxic damage in the CA3 hippocampal subfield, with lower levels of cell death and neurodegeneration, compared to controls. In CA4, the results were not conclusive, and no damage was observed in CA1 after KA administration. PRL treatment provoked an upregulation of active Akt, a well-known cell survival pathway, after KA administration. PRL also caused downregulation of active MAPK, independently of the excitotoxic damage. The present results indicate a neuroprotective role for PRL preferentially located in the CA3 area of the hippocampus of male mice, possibly mediated by Akt-related survival mechanisms.

Neuron loss associated with age but not Alzheimer's disease pathology in the chimpanzee brain.

In the absence of disease, ageing in the human brain is accompanied by mild cognitive dysfunction, gradual volumetric atrophy, a lack of significant cell loss, moderate neuroinflammation, and an increase in the amyloid beta (Aβ) and tau proteins. Conversely, pathologic age-related conditions, particularly Alzheimer's disease (AD), result in extensive neocortical and hippocampal atrophy, neuron death, substantial Aβ plaque and tau-associated neurofibrillary tangle pathologies, glial activation and severe cognitive decline. Humans are considered uniquely susceptible to neurodegenerative disorders, although recent studies have revealed Aβ and tau pathology in non-human primate brains. Here, we investigate the effect of age and AD-like pathology on cell density in a large sample of postmortem chimpanzee brains (n = 28, ages 12-62 years). Using a stereologic, unbiased design, we quantified neuron density, glia density and glia:neuron ratio in the dorsolateral prefrontal cortex, middle temporal gyrus, and CA1 and CA3 hippocampal subfields. Ageing was associated with decreased CA1 and CA3 neuron densities, while AD pathologies were not correlated with changes in neuron or glia densities. Differing from cerebral ageing and AD in humans, these data indicate that chimpanzees exhibit regional neuron loss with ageing but appear protected from the severe cell death found in AD. This article is part of the theme issue 'Evolution of the primate ageing process'.

Time-Dependent Impairment of Fear Conditioning and Associated Brain Regions After Pilocarpine-Induced Status Epilepticus.

Our study aimed to demonstrate time-dependent declarative memory changes and its associated brain regions after status epilepticus (SE) using structural imaging techniques and machine learning methods. Pilocarpine was administrated to establish the SE model. At four different time points after SE (1, 2, 3, and 4 months, respectively), rats were subjected to structural imaging acquisition as well as contextual fear conditioning for the measurement of brain structural changes and declarative memory. Voxel-based morphometry (VBM) analysis were performed. Those significantly different regions were selected as features for training support vector machine (SVM). A linear kernel was chosen for regression of declarative memory. Leave-one-out cross-validation was applied to ensure generalization. Our results showed that the pilocarpine groups displayed the most severely impaired declarative memory at 2 months after SE and improved afterward, but failed to recover to the normal condition at 4 months after SE. The pilocarpine groups showed lower gray matter volumes and larger cerebrospinal fluid (CSF) volumes. After controlling for the total brain volumes, ANOVA demonstrated gray matter volume changes in the CA1 subfield of the hippocampus, primary somatosensory cortex, entorhinal cortex, etc. The combination of VBM and SVM identifies the somatosensory cortex and entorhinal cortex as the correlated brain regions for declarative memory dysfunctions after SE. Our study indicates that compensational mechanisms might be triggered to help with the recovery of memory functions after SE. Structural changes of the somatosensory cortex and entorhinal cortex might be involved in memory impairment after SE.

Afterhyperpolarization amplitude in CA1 pyramidal cells of aged Long-Evans rats characterized for individual differences

Altered neural excitability is considered a prominent contributing factor to cognitive decline during aging. A clear example is the excess neural activity observed in several temporal lobe structures of cognitively impaired older individuals in rodents and humans. At a cellular level, aging-related changes in mechanisms regulating intrinsic excitability have been well examined in pyramidal cells of the CA1 hippocampal subfield. Studies in the inbred Fisher 344 rat strain document an age-related increase in the slow afterhyperpolarization (AHP) that normally occurs after a burst of action potentials, and serves to reduce subsequent firing. We evaluated the status of the AHP in the outbred Long-Evans rat, a well-established model for studying individual differences in neurocognitive aging. In contrast to the findings reported in the Fisher 344 rats, in the Long-Evan rats we detected a selective reduction in AHP in cognitively impaired aged individuals. We discuss plausible scenarios to account for these differences and also discuss possible implications of these differences.

Prolactin treatment reduces kainic acid-induced gliosis in the hippocampus of ovariectomized female rats

Neuroinflammation involves a set of responses occurring as a result of brain damage including astro- and microgliosis. In previous studies, we showed that treatment with prolactin (PRL) decreased neuronal loss induced by kainic acid (KA) in the hippocampus of female rats. This effect correlated with a decrease in astrogliosis. Here, we investigate whether treatment with PRL decreases astro- and microgliosis in the dorsal hippocampus, and how it modulates the expression of some important inflammatory factors such as TNFα, iNOS, IL-6, IL-10 and IL-4 after an excitotoxic lesion. For this, ovariectomized female rats were treated chronically with PRL (0.1 mg / day for 4 days, SC). On the third day of treatment, they received a KA injection (7.5 mg / kg, IP) and were sacrificed 24 or 48 h later. Chronic treatment with PRL reduced the astro- and micro-gliosis in CA4, CA3, and CA1 hippocampal subfields induced by KA. Morphometric analysis in CA4 showed that PRL reduced microglial activation. The analysis for anti- and pro-inflammatory cytokines revealed an increase of IL-10 and IL-4 in neurons due to treatment with PRL, accompanied by a decrease in the expression of TNFα and iNOS in lesioned rats. These results indicate that PRL has anti-inflammatory actions in the hippocampus, both by decreasing the astrogliosis and microglial activation and by reducing the level of pro-inflammatory cytokines probably through the upregulation of neuronal IL-10 and IL-4.

Simulations reveal how M-currents and memory-based inputs from CA3 enable single neuron mismatch detection for EC3 inputs to the CA1 subfield of hippocampus

Significant evidence has accumulated to support the hypothesis that hippocampal region CA1 operates as an associative mismatch detector (e.g., Hasselmo ME, Schnell E, Barkai E. J Neurosci 15: 5249-5262, 1995; Duncan K, Curtis C, Davachi L. J Neurosci 29: 131-139, 2009; Kumaran D, Maguire EA. J Neurosci 27: 8517-8524, 2007; Lisman JE, Grace AA. Neuron 46: 703-713, 2005; Lisman JE, Otmakhova NA. Hippocampus 11: 551-568 2001; Lörincz A, Buzsáki G. Ann N Y Acad Sci 911: 83-111, 2000; Meeter M, Murre JMJ, Talamini LM. Hippocampus 14: 722-741, 2004; Schiffer AM, Ahlheim C, Wurm MF, Schubotz RI. PLoS One 7: e36445, 2012; Vinogradova OS. Hippocampus 11: 578-598 2001). CA1 compares predictive synaptic signals from CA3 with synaptic signals from EC3, which reflect actual sensory inputs. The new CA1 pyramidal model presented here shows that the distal-proximal segregation of synaptic inputs from EC3 versus CA3, along with other biophysical features, enable such pyramids to serve as comparators that switch output encoding from a brief burst, for a match, to prolonged tonic spiking, for a mismatch. By including often-overlooked features of CA1 pyramidal neurons, this new model allows simulation of pharmacological effects that can eliminate either the match (phasic mode) response or the mismatch (tonic mode) response. These simulations reveal that dysfunctions can arise from either too much or too little ACh stimulation of the muscarinic receptors that control KCNQ channels. Additionally, a dysfunction caused by administration of an N-methyl-d-aspartate antagonist could be rescued by simultaneous administration of a KCNQ channel agonist, such as retigabine.NEW & NOTEWORTHY Hippocampal region CA1 operates as an associative mismatch detector, comparing predictive signals from CA3 with signals from EC3 reflecting sensory inputs. This new CA1 pyramidal model shows that biophysical features enable these comparators to switch output between brief bursts for matches and tonic spiking for mismatches. This suggests that cognitive learning models (e.g., predictive coding) may require much less match/mismatch circuitry than commonly assumed. Additional simulations illuminate deficits seen in psychiatric disorders and drug-induced states.

Androgen Affects the Dynamics of Intrinsic Plasticity of Pyramidal Neurons in the CA1 Hippocampal Subfield in Adolescent Male Rats

Androgen receptor (AR) is abundantly expressed in the preoptico-hypothalamic area, bed nucleus of stria terminalis, and medial amygdala of the brain where androgen plays an important role in regulating male sociosexual, emotional and aggressive behaviors. In addition to these brain regions, AR is also highly expressed in the hippocampus, suggesting that the hippocampus is another major target of androgenic modulation. It is known that androgen can modulate synaptic plasticity in the CA1 hippocampal subfield. However, to date, the effects of androgen on the intrinsic plasticity of hippocampal neurons have not been clearly elucidated. In this study, the effects of androgen on the expression of AR in the hippocampus and on the dynamics of intrinsic plasticity of CA1 pyramidal neurons were examined using immunohistochemistry, Western blotting and whole-cell current-clamp recording in unoperated, sham-operated, orchiectomized (OCX), OCX + testosterone (T) or OCX + dihydrotestosterone (DHT)-primed adolescent male rats. Orchiectomy significantly decreased AR-immunoreactivity, resting membrane potential, action potential numbers, afterhyperpolarization amplitude and membrane resistance, whereas it significantly increased action potential threshold and membrane capacitance. These effects were successfully reversed by treatment with either aromatizable androgen T or non-aromatizable androgen DHT. Furthermore, administration of the AR-antagonist flutamide in intact rats showed similar changes to those in OCX rats, suggesting that androgens affect the excitability of CA1 pyramidal neurons possibly by acting on the AR. Our current study potentially clarifies the role of androgen in enhancing the basal excitability of the CA1 pyramidal neurons, which may influence selective neuronal excitation/activation to modulate certain hippocampal functions.

Smaller left hippocampal subfield CA1 volume is associated with reported childhood physical and/or sexual abuse in major depression: A pilot study

BackgroundSmaller hippocampal volumes are reported in adults with major depressive disorder (MDD) and in reported childhood abuse. The hippocampus is a complex structure with distinct functional subfields. We sought to examine the effect of MDD diagnosis and childhood abuse on hippocampal subfields. MethodsForty-one MDD participants (17 reported abuse and 24 did not) and 46 healthy volunteers (HV) (2 reported abuse) underwent T1- weighted structural magnetic resonance imaging (MRI) and clinical characterization in a retrospective design. A subfield segmentation program was used to measure the whole and subfield hippocampal volumes. Linear mixed-effects models were fitted for group comparisons. ResultsNo main effect of diagnosis interaction effect between diagnosis and subfield region was observed. However, a comparison of abused MDD vs. HVs showed a group by region interaction. A significant interaction between childhood abuse and region was observed. Effects were confined to the left side of the brain, and post hoc, exploratory region-specific tests indicated smaller left CA1 volume in abused MDD compared with non-abused MDD. In addition, smaller amygdala volume was found in all MDD compared with HVs. LimitationsWe did not have a sample of healthy volunteers with reported childhood abuse. ConclusionsThe diagnosis of pure MDD may not be sufficient to exert effects on hippocampal volumes, indicating the importance of taking into account childhood trauma in studies on psychopathological mechanisms. Left CA1 might be the hippocampal subfield most relevant to reported childhood abuse. Smaller amygdala volume may be related to MDD diagnosis independent of childhood abuse.