CA1

The hippocampus is one of the few brain areas that has a highly linear feed-forward network architecture. Despite massive efforts to unravel hippocampal mnemonic function through pharmacological, genetic, electrophysiological, lesion, and modeling studies, the role of the hippocampal network is still unknown. In this work, I propose to explain the role of the hippocampus in classical conditioning by assuming that CA1 is a temporal calculator and CA3 is an autoassociator. I developed a computational model in MatLab based on these proposed roles of CA3 and CA1. The validity of the model was first tested by comparing generated results with available published data. The results of the model were then used to generate several predictions that can be experimentally verified through electrophysiological or behavioral experiments.

This review summarizes the structural and electrophysiological changes in the epileptic hippocampus in various animal models of epilepsy. Tornado hypothesis of epileptic hippocampus, states that there are many progressive detrimental changes in the hippocampus of the epileptic rats. PTZ, PTZ kindling, pilocarpine, electrical kindling, kainic acid, hyperthermia and in vitro models are taken as primary animal epilepsy models in this review. Paired pulse inhibition and GABAergic transmission is decreased in dentate gyrus (DG), CA3 and CA1 regions of the epileptic hippocampus. There is interneuron loss in the hilus, DG and CA3, while excitatory input from perforant path (PP) is increased and this is fed into the CA3 area by mossy fibers (MF) which have excessive sprouting that forms novel recurrent synapses with the pyramidal cells of CA3. Gate function of DG is either impaired or lost. CA3 area of hippocampus becomes an epileptic focus and sends ictal discharges. These ictal discharges are carried into CA1 by Schaffer collaterals and then into entorhinal cortex (EC). The input from EC is amplified in the hippocampal circuitry which is fed into hippocampus from EC into DG again successively. Thus, a weak electrical input into the hippocampal formation results in an amplified signal back into EC. Since the basic ultrastructural and electrophysiological feedback control mechanisms are impaired, this electrical tornado cannot be compensated for and an epileptic amplified ictal discharge spreads to the limbic system and other adjacent structures of the brain. Eventually the hippocampal circuitry, that has developed a vicious circle, becomes a bio-electrical amplifier which triggers an electrical tornado, under certain biochemical conditions. mossy fiber sprouting, in vitro model of epilepsy, perforant path, tonic clonic seizures, intractable temporal lobe epilepsy.

Identifying the specific substrates of memory deficits in early Alzheimer's disease would help to develop clinically-relevant therapies. The present study assesses the relationships between encoding versus retrieval deficits in patients with amnestic Mild Cognitive Impairment (aMCI) and atrophy specifically within the hippocampus and throughout the white matter. Twenty-two aMCI patients underwent T1-weighted MRI scans and neuropsychological testing. Grey matter and white matter segments obtained from the MRI images were each entered in correlation analyses, assessed only in the hippocampus for grey matter segments, with encoding and retrieval memory performances. For the grey matter segments, the resulting spmT correlation maps were then superimposed onto a 3D surface view of the hippocampus to identify the relative involvement of the different subfields, a method already used and validated elsewhere. Memory encoding deficits specifically correlated with CA1 subfield atrophy, while no relationship was found with white matter atrophy. In contrast, retrieval deficits were weakly related to hippocampal atrophy and did not involve a particular subfield, while they strongly correlated with loss of white matter, specifically in medial parietal and frontal areas. In aMCI patients, encoding impairment appears specifically related to atrophy of the CA1 hippocampal subfield, consistent with the predominance of encoding deficits and CA1 atrophy in aMCI. In contrast, episodic retrieval deficits seem to be underlain by more distributed tissue losses, consistent with a disruption of a hippocampo-parieto-frontal network.

Development and implementation of microarray
techniques to quantify expression levels of dozens to hundreds
to thousands of transcripts simultaneously within select tissue
samples from normal control subjects and neurodegenerative
diseased brains has enabled scientists to create molecular fingerprints
of vulnerable neuronal populations in Alzheimer’s
disease (AD) and related disorders. A goal is to sample gene
expression from homogeneous cell types within a defined region
without potential contamination by expression profiles of
adjacent neuronal subpopulations and nonneuronal cells. The
precise resolution afforded by single cell and population cell
RNA analysis in combination with microarrays and real-time
quantitative polymerase chain reaction (qPCR)–based analyses
allows for relative gene expression level comparisons across
cell types under different experimental conditions and disease
progression. The ability to analyze single cells is an important
distinction from global and regional assessments of mRNA
expression and can be applied to optimally prepared tissues
from animal models of neurodegeneration as well as postmortem
human brain tissues. Gene expression analysis in postmortem
AD brain regions including the hippocampal formation and
neocortex reveals selectively vulnerable cell types share putative
pathogenetic alterations in common classes of transcripts,
for example, markers of glutamatergic neurotransmission, synaptic-
related markers, protein phosphatases and kinases, and
neurotrophins/neurotrophin receptors. Expression profiles of
vulnerable regions and neurons may reveal important clues
toward the understanding of the molecular pathogenesis of
various neurological diseases and aid in identifying rational
targets toward pharmacotherapeutic interventions for progressive,
late-onset neurodegenerative disorders such as mild cognitive
impairment (MCI) and AD. Key Words: Microarray,
neurodegeneration, RNA amplification, aging, qPCR, mild
cognitive impairment, molecular fingerprint, postmortem human
brain.

Subregional analyses of the hippocampus suggest CA1-dependent memory processes rely heavily upon interactions between the CA1 subregion and entorhinal cortex. There is evidence that the direct perforant path (pp) projection to CA1 is selectively modulated by dopamine while having little to no effect on the Schaffer collateral (SC) projection to CA1. The current study takes advantage of this pharmacological dissociation to demonstrate that local infusion of the non-selective dopamine agonist, apomorphine (10, 15 µg), into the CA1 subregion of awake animals produces impairments in working memory at intermediate (5 min), but not short-term (10 sec) delays within a delayed nonmatch-to-place task on a radial arm maze. Sustained impairments were also found in a novel context with similar object-space relationships. Infusion of apomorphine into CA1 is also shown here to produce deficits in spatial, but not non-spatial novelty detection within an object exploration paradigm. In contrast, apomorphine produces no behavioral deficits when infused into the CA3 subregion or overlying cortex. These behavioral studies are supported by previous electrophysiological data that demonstrate local infusion of the same doses of apomorphine significantly modifies evoked responses in the distal dendrites of CA1 following angular bundle stimulation, but produces no significant effects in the proximal dendritic layer following stimulation of the SC. These results support a modulatory role for dopamine in EC-CA1, but not CA3-CA1 circuitry, and suggest the possibility of a fundamental role for EC-CA1 synaptic transmission in terms of detection of spatial novelty, and intermediate-term, but not short-term spatial working memory or object-novelty detection.

Down syndrome (DS) is the most prevalent cause of intellectual
disability (ID). Individuals with DS show a variety
of cognitive deficits, most notably in hippocampal learning
and memory, and display pathological hallmarks of
Alzheimer’s disease (AD), with neurodegeneration of cholinergic
basal forebrain (CBF) neurons. Elucidation of the
molecular and cellular underpinnings of neuropathology
has been assessed via gene expression analysis in a relevant
animal model, termed the Ts65Dn mouse. The
Ts65Dn mouse is a segmental trisomy model of DS that
mimics DS/AD pathology, notably age-related cognitive
dysfunction and degeneration of basal forebrain cholinergic
neurons (BFCNs). To determine expression level
changes, molecular fingerprinting of cornu ammonis 1
(CA1) pyramidal neurons was performed in adult (4–9
month-old) Ts65Dn mice, at the initiation of BFCN degeneration.
To quantitate transcriptomic changes during this
early time period, laser capture microdissection (LCM),
terminal continuation (TC) RNA amplification, customdesigned
microarray analysis, and subsequent validation
of individual transcripts by qPCR and protein analysis via
immunoblotting was performed. The results indicate significant
alterations within CA1 pyramidal neurons of
Ts65Dn mice compared with normal disomic (2N) littermates,
notably in the downregulation of neurotrophins
and their cognate neurotrophin receptors among other
classes of transcripts relevant to neurodegeneration. The
results of this single-population gene expression analysis
at the time of septohippocampal deficits in a trisomic
mouse model shed light on a vulnerable circuit that may
cause the AD-like pathology invariably seen in DS that
could help to identify mechanisms of degeneration, and
provide novel gene targets for therapeutic interventions.

Mood disorders are associated to functional unbalance in mesolimbic and frontal cortical circuits. As a commonly used mood stabilizer, lithium acts through multiple biochemical pathways, including those activated by muscarinic cholinergic receptors crucial for hippocampal-prefrontal communication. Therefore, here we investigated the effects of lithium on prefrontal cortex responses under cholinergic drive. Lithium-treated rats were anesthetized with urethane and implanted with a ventricular cannula for muscarinic activation, a recording electrode in the medial prefrontal cortex (mPFC), and a stimulating electrode in the intermediate hippocampal CA1. Either of two forms of synaptic plasticity, long-term potentiation (LTP) or depression (LTD), were induced during pilocarpine effects, which were monitored in real time through local field potentials. We found that lithium attenuates the muscarinic potentiation of cortical LTP (<20 min) but enhances the muscarinic potentiation of LTD maintenance (>80 min). Moreover, lithium treatment promoted significant cross-frequency coupling between CA1 theta (3–5 Hz) and mPFC low-gamma (30–55 Hz) oscillations. Interestingly, lithium by itself did not affect any of these measures. Thus, lithium pretreatment and muscarinic activation synergistically modulate the hippocampal-prefrontal connectivity. Because these alterations varied with time, oscillatory parameters, and type of synaptic plasticity, our study suggests that lithium influences prefrontal-related circuits through intricate dynamics, informing future experiments on mood disorders.

To evaluate molecular signatures of an individual cell type in comparison to the associated region relevant
towards understanding the pathogenesis of Alzheimer's disease (AD), CA1 pyramidal neurons and the
surrounding hippocampal formation were microaspirated via laser capture microdissection (LCM) from
neuropathologically confirmed AD and age-matched control (CTR) subjects as well as from wild type mouse
brain using single population RNA amplification methodology coupled with custom-designed microarray
analysis with real-time quantitative polymerase-chain reaction (qPCR) validation. CA1 pyramidal neurons
predominantly displayed downregulation of classes of transcripts related to synaptic transmission in AD
versus CTR. Regional hippocampal dissections displayed downregulation of several overlapping genes found
in the CA1 neuronal population related to neuronal expression, as well as upregulation of select transcripts
indicative of admixed cell types including glial-associated markers and immediate-early and cell death genes.
Gene level distributions observed in CA1 neurons and regional hippocampal dissections in wild type mice
paralleled expression mosaics seen in postmortem human tissue. Microarray analysis was validated in qPCR
studies using human postmortem brain tissue and CA1 sector and regional hippocampal dissections obtained
from a mouse model of AD/Down syndrome (Ts65Dn mice) and normal disomic (2N) littermates. Classes of
transcripts that have a greater percentage of the overall hybridization signal intensity within single neurons
tended to be genes related to neuronal communication. The converse was also found, as classes of transcripts
such as glial-associatedmarkers were under represented in CA1 pyramidal neuron expression profiles relative
to regional hippocampal dissections. These observations highlight a dilution effect that is likely to occur in
conventional regional microarray and qPCR studies. Thus, single population studies of specific neurons and
intrinsic circuits will likely yield informative gene expression profile data that may be subthreshold and/or
underrepresented in regional studies with an admixture of cell types.

The use of five histochemical stains (cresyl violet, thionin, hematoxylin & eosin, silver stain, and acridine
orange) was evaluated in combination with an expression profiling paradigm that included regional and single
cell analyses within the hippocampus of post-mortem human brains and adult mice. Adjacent serial sections of
human and mouse hippocampus were labeled by histochemistry or neurofilament immunocytochemistry.
These tissue sections were used as starting material for regional and single cell microdissection followed by a
newly developed RNA amplification procedure (terminal continuation (TC) RNA amplification) and subsequent
hybridization to custom-designed cDNA arrays. Results indicated equivalent levels of global hybridization
signal intensity and relative expression levels for individual genes for hippocampi stained by cresyl violet,
thionin, and hematoxylin & eosin, and neurofilament immunocytochemistry. Moreover, no significant
differences existed between the Nissl stains and neurofilament immunocytochemistry for individual CA1
neurons obtained via laser capture microdissection. In contrast, a marked decrement was observed in adjacent
hippocampal sections stained for silver stain and acridine orange, both at the level of the regional dissection
and at the CA1 neuron population level. Observations made on the cDNA array platform were validated by realtime
qPCR using primers directed against b-actin and glyceraldehyde-3 phosphate dehydrogenase. Thus, this
report demonstrated the utility of using specific Nissl stains, but not stains that bind RNA species directly,
in both human and mouse brain tissues at the regional and cellular level for state-of-the-art molecular
fingerprinting studies.

Environmental enrichment promotes structural and functional changes in the brain, including enhanced learning and memory performance in rodents. Transient global cerebral ischemia (15 min) causes specific damage to dorsal hippocampal area CA1 pyramidal cells of the rat concomitantly with cognitive deficits. Thus, we investigated if environmental enrichment can protect rats against the cognitive and neurological consequences of transient ischemia. We evaluated the impairment of learning and memory with three tasks: odour discrimination, object exploration and spatial learning. Contrary to expectation, we found that the enriched environment improved performances for both ischemic and sham rats in odour discrimination and object exploration tasks compared with standard condition housed rats. After exposure to an enriched environment, ischemic rats performed better in the water maze than those in the standard housing conditions. However, exposure to an enriched environment does not protect against actual loss of CA1 pyramidal cells. Brain-derived neurotrophic factor (BDNF) levels were increased in environmental enrichment animals compared to those housed in standard conditions. We conclude that environmental enrichment has positive effects that are independent of the effects of ischemic brain lesions.

Recent advances in neuroimaging have highlighted the interest to differentiate hippocampal subfields for cognitive neurosciences and more notably in assessing the effects of normal and pathological aging. The main goal of the present study is to investigate the effects of normal aging onto the volume of the different hippocampal subfields. For this purpose, we developed a new magnetic resonance sequence together with reliable tracing guidelines to assess the volume of different subfields of the hippocampus using a 3 Tesla scanner, and estimated the validity of a simpler and less time-consuming method based on the widely-used automatic Voxel-Based Morphometry (VBM) technique. Three hippocampal regions of interest were delineated on the right and left hippocampi of 50 healthy subjects between 18 and 68 years old corresponding to the CA1, subiculum and other (including CA2-3-4 and Dentate Gyrus) subfields. A strong effect of age was found on the volume of the subiculum only, with a decrease paralleling that of the global gray matter volume, while CA1 and other subfields seemed relatively spared. Although less precise than the ROI-tracing technique, the VBM-based method appeared as a reliable alternative especially to distinguish CA1 and subiculum subfields. Our findings of a specific effect of age on the subiculum are consistent with the developmental hypothesis ("last-in first-out" theory). This contrasts with the predominant vulnerability of the CA1 subfield to Alzheimer's disease reported in several previous studies, suggesting that the assessment of hippocampal subfields may improve the discrimination between normal and pathological aging.