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PubMed2005

Beyond two-cell networks: experimental measurement of neuronal responses to multiple synaptic inputs.

Oscillations of large populations of neurons are thought to be important in the normal functioning of the brain. We have used phase response curve (PRC) methods to characterize the dynamics of single neurons and predict population dynamics. Our past experimental work was limited to special circumstances (e.g., 2-cell networks of periodically firing neurons). Here, we explore the feasibility of extending our methods to predict the synchronization properties of stellate cells (SCs) in the rat entorhinal cortex under broader conditions. In particular, we test the hypothesis that PRCs in SCs scale linearly with changes in synaptic amplitude, and measure how well responses to Poisson process-driven inputs can be predicted in terms of PRCs. Although we see nonlinear responses to excitatory and inhibitory inputs, we find that models based on weak coupling account for scaling and Poisson process-driven inputs reasonably accurately.

Animals↗
PubMedDate not supplied

Beta-amyloid deposition and other measures of neuropathology predict cognitive status in Alzheimer's disease.

The relationship between progressive cognitive decline and underlying neuropathology associated with Alzheimer s disease (AD) is a key issue in defining the mechanisms responsible for functional loss. This has been a subject of much controversy, with separate studies comparing various clinical and neuropathological indices in AD. Further, it is difficult to compare studies with differences in histochemical staining protocols, brain regions examined, and data quantification criteria. There are many difficulties in designing a clinical-pathological correlative study involving AD patients. It is necessary to control for several key parameters. For example, a broad range of cognitively impaired subjects is needed, as well as short postmortem delays, brief intervals between cognitive testing and death, and the most sensitive detection and quantification techniques. In this study, we carefully controlled for each of these parameters to determine if there is a relationship between global cognitive dysfunction and multiple neuropathological indices. We selected 20 individuals representing a broad range of cognitive ability from normal to severely impaired based on the MMSE, Blessed IMC, and CDR. We counted plaque number, NFT number, dystrophic neurite number, and the relative extent of thioflavine positive plaques and neuritic involvement within plaques. We also quantified cortical area occupied by beta-amyloid immunoreactivity (A beta Load) and PHF-1 positive neuropil threads and tangles (PHF Load) using computer-based image analysis. Interestingly, we found that most pathologic measures correlated highly with the severity of dementia. However, the strongest predictor of premortem cognitive dysfunction on all three cognitive measures was the relative area of entorhinal cortex occupied by beta-amyloid deposition. In conclusion, our data show that in a carefully controlled correlative study, a variety of neuropathological variables are strongly correlated with cognitive impairment. Plaque related variables may be as strongly related to cognitive dysfunction as other established measures, including synapse loss, cell death and tau hyperphosphorylation, although no correlative study can demonstrate causality.

Aged↗
PubMed1999

The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit.

While homomers containing 5-HT(3A) subunits form functional ligand-gated serotonin (5-HT) receptors in heterologous expression systems (Jackson, M. B., and Yakel, J. L. (1995) Annu. Rev. Physiol. 57, 447-468; Lambert, J. J., Peters, J. A., and Hope, A. G. (1995) in Ligand-Voltage-Gated Ion Channels (North, R., ed) pp. 177-211, CRC Press, Inc., Boca Raton, FL), it has been proposed that native receptors may exist as heteromers (Fletcher, S., and Barnes, N. M. (1998) Trends Pharmacol. Sci. 19, 212-215). We report the cloning of a subunit 5-HT(3B) with approximately 44% amino acid identity to 5-HT(3A) that specifically modified 5-HT(3A) receptor kinetics, voltage dependence, and pharmacology. Co-expression of 5-HT(3B) with 5-HT(3A) modified the duration of 5-HT(3) receptor agonist-induced responses, linearized the current-voltage relationship, increased agonist and antagonist affinity, and reduced cooperativity between subunits. Reverse transcriptase-polymerase chain reaction in situ hybridization revealed co-localization of both 5-HT(3B) and 5-HT(3A) in a population of neurons in the amygdala, telencephalon, and entorhinal cortex. Furthermore, 5-HT(3A) and 5-HT(3B) mRNAs were expressed in spleen and intestine. Our data suggest that 5-HT(3B) might contribute to tissue-specific functional changes in 5-HT(3)-mediated signaling and/or modulation.

Amygdala↗
PubMed1994

Dopamine D2 receptor expression in hippocampus and parahippocampal cortex of rat, cat, and human in relation to tyrosine hydroxylase-immunoreactive fibers.

A detailed study comparing the distribution of D2 receptors and tyrosine hydroxylase-immunoreactive fibers in the hippocampus and parahippocampal cortices of the rat, cat, and human was conducted. The distribution of [125I]epidepride binding to D2 receptors along the transverse and longitudinal axes of the hippocampus and parahippocampus differed among the species. In rat hippocampus, the number of sites was highest in septal portions of lacunosum-moleculare of CA1 and stratum moleculare of the subiculum. Virtually no binding to D2 receptors existed in the temporal hippocampus. For the cat hippocampus, the highest binding existed in the inner one-third of the molecular layer of the dentate gyrus (DG). There were also significant numbers of D2 receptors in strata radiatum and oriens of the CA subfields, with almost undetectable levels in lacunosum moleculare and subiculum. The number of sites was higher in the septal than temporal hippocampus. In the human hippocampus, highest binding was observed in the molecular layer of DG and the subiculum, with lower levels in strata oriens and lacunosum-moleculare of CA3, and very low binding in CA1. The histochemical demonstration of the pattern of mossy fibers revealed an organization complementary to that of D2 receptors in cat and human. In none of the species was there significant expression of D2 receptors in the entorhinal cortex, except in the caudal extreme of this region in the rat. In that region a trilaminar pattern was exhibited that continued into the perirhinal cortex. A trilaminar pattern of D2 receptor expression was observed in the perirhinal cortex of all species, with the highest values in the external and deep laminae and low expression in the middle laminae. The organization of dopamine fibers was assessed by comparing the distribution of tyrosine hydroxylase-positive and dopamine beta-hydroxylase-immunoreactive fibers in these same regions. It revealed consistent mismatches between the pattern of D2 receptor expression and dopaminergic innervation in all three species. The implications for this mismatch are discussed. It is hypothesized that the distribution of D2 receptors, and not of dopamine fibers, determines what neural systems dopamine influences in the hippocampal complex.

Aged↗
PubMed2002

Excitatory and inhibitory control of epileptiform discharges in combined hippocampal/entorhinal cortical slices.

We examined whether epileptiform activity can be induced and prevented by mild reduction of GABA(A) receptor-mediated inhibition and non-NMDA receptor-mediated excitation, respectively, in different regions of combined hippocampal/entorhinal cortical slices from juvenile rats (P15-21). We used the receptor antagonists bicuculline (GABA(A)) and CNQX (non-NMDA) as tools to investigate the sensitivities of the CA1, the subiculum (SUB) and the medial entorhinal cortex (MEC) for generating epileptiform discharges upon extracellular stimulation. We found that low concentrations of bicuculline (<3.5 microM) were enough to induce epileptiform discharges in the three regions. These discharges were similar to those observed under high concentrations of bicuculline (>10 microM) and consisted of stereotyped population bursts, recorded both extra- and intracellularly. Interestingly, the CA1 and SUB were more susceptible to generate discharges compared to the MEC in the same slices. We also found that non-NMDA excitation was critical in controlling discharges, as they were blocked by CNQX in a concentration-dependent manner. The sensitivity of the CA1 region to CNQX was lower than that of the SUB and MEC. Based on these regional differences, we show that epileptiform activity can be pharmacologically isolated within the CA1 region in the hippocampal-entorhinal circuitry in vitro.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2002

The influence of selective lesions to components of the hippocampal system on the orienting [correction of orientating] response, habituation and latent inhibition.

The contribution that components of the hippocampal system in the rat make to the modulation of attention or stimulus processing was assessed using several simple behavioural assays: the orienting response (OR) to a novel stimulus, the subsequent habituation and dishabituation of this OR, and the latent inhibition effect that typically results from repeated exposure to a stimulus. Excitotoxic lesions of components of the hippocampal system produce dissociable effects on the OR, habituation and latent inhibition: lesions of the entorhinal cortex have no effect on the OR or changes in the OR during exposure to a stimulus, but disrupt latent inhibition; lesions of the subiculum disrupt the OR but not latent inhibition; and lesions of the hippocampus disrupt the OR and latent inhibition. These effects have important implications for our understanding of habituation and latent inhibition, and the neural mechanisms involved in attentional modulation.

Animals↗
PubMed1994

Production and characterization of polyclonal antibodies recognizing the intracytoplasmic third loop of the 5-hydroxytryptamine1A receptor.

The portion of the complementary DNA encoding the third intracellular loop of the rat 5-hydroxytryptamine1A (serotonin) receptor was subcloned into the vector pGEX-KG and expressed in Escherichia coli as a fusion protein coupled with the glutathione S-transferase of Schistosoma japonicum. The fusion protein was purified on a glutathione-agarose affinity column and used to immunize rabbits for the production of polyclonal anti-5-hydroxytryptamine1A receptor antibodies. Enzyme-linked immunosorbent assay revealed that antibodies were produced as early as one month after the first injection of the fusion protein, and immune response plateaued at a maximum after the third (monthly) booster injection. These antibodies only marginally affected the specific binding of [3H]8-hydroxy-2-(di-n-propyl-amino) tetralin to solubilized and membrane bound 5-hydroxytryptamine1A receptors, and did not interfere with serotonin-induced inhibition of forskolin-stimulated adenylate cyclase negatively coupled to 5-hydroxytryptamine1A receptors in rat hippocampal membranes. However, antibodies were able to immunoprecipitate 5-hydroxytryptamine1A receptor binding sites solubilized from rat hippocampal membranes. The distribution of immunoautoradiographic labelling and immunohistochemical staining of rat brain sections exposed to the antibodies raised against the fusion protein superimposed to that of 5-hydroxytryptamine1A receptor binding sites labelled by specific radioligands, with marked enrichment in the limbic areas (dentate gyrus and CA1 area in the hippocampus, lateral septum, entorhinal cortex) and the anterior raphe nuclei. The differential cellular location of immunoreactivity within the hippocampus (where dendritic fields but not pyramidal cell somas were immunostained) and the median raphe nucleus (where the plasmic membrane of somas was strongly immunoreactive) suggests that the addressing of 5-hydroxytryptamine1A receptors might differ from one neuronal cell type to another.

Adenylyl Cyclases↗
PubMed2003

Alzheimer's disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor immunoreactivity in astrocytes.

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are common forms of dementia in the elderly associated with cholinergic dysfunction, including reductions in nicotinic acetylcholine receptors (nAChRs). In AD, astrocytes are implicated in the formation of senile plaques, one of the core pathological features. Using immunohistochemistry, we have investigated astrocytic expression of the two major nicotinic receptor alpha subunits in the human hippocampus and entorhinal cortex. alpha7, but not alpha4, subunit immunoreactivity was associated with astrocytes. An increase in the proportion of astrocytes expressing alpha7 immunoreactivity was observed in AD compared with age-matched controls. A similar increase was not evident in DLB. Elevated alpha7 nAChRs on astrocytes in AD may contribute to alterations in calcium homeostasis and nitric oxide production, which in turn could affect beta-amyloid-mediated inflammatory processes in AD.

Aged↗
PubMed2006

From grids to places.

Hafting et al. (2005) described grid cells in the dorsocaudal region of the medial entorhinal cortex (dMEC). These cells show a strikingly regular grid-like firing-pattern as a function of the position of a rat in an enclosure. Since the dMEC projects to the hippocampal areas containing the well-known place cells, the question arises whether and how the localized responses of the latter can emerge based on the output of grid cells. Here, we show that, starting with simulated grid-cells, a simple linear transformation maximizing sparseness leads to a localized representation similar to place fields.

Action Potentials↗
PubMed1996

Increased susceptibility of brain slices from carbonic anhydrase II-deficient mice to low [Mg2+]O-induced seizures.

Brain pH is thought to be an influential factor in determining susceptibility to seizures. We compared the susceptibility of brain slices from carbonic anhydrase II (CA II)-deficient mice to epileptiform activity induced by low extracellular [Mg2+], with slices from normal littermates, both bathed in artificial cerebrospinal fluid at pH 7.3. In both entorhinal cortex and hippocampal field CA1, epileptiform activity started earlier in CA II-deficient slices. Raising extracellular [CO2] (20%; extracellular pH, 6.7) reversibly blocked the epileptiform activity in normal, but not in CA II-deficient, slices. The data, combined with previous in vivo findings showing an increased resistance of mutants to seizures, suggest the presence of in vivo anticonvulsant acidosis with long-term compensatory changes that lead to in vitro 'proconvulsant' behavior in CA II-deficient slices clamped at pH 7.3.

Animals↗
PubMed2000

A functional genomic study of the effects of antipsychotic agent chlorpromazine in PC12 cells.

Expression profiling using methods of functional genomics can be used to investigate changes in gene transcription induced by drug treatment, which may lead to discovery of new potential drug targets. Antipsychotic agents alleviate symptoms of schizophrenia but the mechanism behind their clinical efficacy is unclear. We have used the PC12 cell line as a model to characterize effects of the antipsychotic drug chlorpromazine on gene expression using high-density complementary DNA array filters prepared from a rat brain entorhinal cortex complementary DNA library. Chlorpromazine treatment positively regulated the expression of several clones, five of which were selected for further characterization. Northern blotting experiments confirmed the increased expression of these genes after chlorpromazine treatment. Sequencing revealed that two clones were cytochrome c oxidase and three were novel genes. Characterization of the function of these genes could increase our understanding of the mechanisms of action of antipsychotic drugs, and might be beneficial for the development of more effective agents.

Animals↗
PubMed2004

Cocaine alters GABA(B)-mediated G-protein activation in the ventral tegmental area of female rats: modulation by estrogen.

In female rats, estrogen has been reported to enhance cocaine sensitization. Here we investigated the effect of estrogen and cocaine treatments on GABA(B)-stimulated [(35)S]GTPgammaS binding. Ovariectomized rats without (OVX) and with estrogen treatment (OVX-EB) were pretreated with saline or cocaine (15 mg/kg, i.p.) for 5 days and after 1 week of withdrawal challenged with cocaine. One hour after the final injection, animals were sacrificed, brains immediately frozen, and stored at -70 degrees C for subsequent cryosectioning. In vitro functional autoradiography was performed using baclofen (300 microM), a GABA(B) receptor agonist, to stimulate [(35)S]GTPgammaS binding in tissue sections at the level of the ventral tegmental area (VTA). OVX-EB rats showed lower levels of [(35)S]GTPgammaS binding in the VTA (-15%) and entorhinal cortex (EC) (-60%). The effect of cocaine on GABA(B)-mediated G-protein activation varied with the presence of estrogen. Repeated cocaine administration reduced [(35)S]GTPgammaS binding in the VTA and EC of OVX rats and increased it in OVX-EB. Thus, our data suggest that estrogen reduces GABA(B)-mediated G-protein activation in female rats. The results also show that estrogen strongly influences cocaine-induced alterations in GABA(B) function in the VTA and EC of female rats.

Animals↗
PubMed2005

The apoE receptor apoER2 is involved in the maintenance of efficient synaptic plasticity.

ApoER2 is one of the major receptors for ApoE in the brain, and has been shown to be involved not only in lipoprotein endocytosis, as other members of the LDL receptor family of receptors, but also in various cellular functions such as signalling and cellular guidance. By using a model of synaptic plasticity in mice lacking none, one or two alleles of the apoER2 gene, we investigated the implication of such a receptor deficiency on the remodelling process. Our results indicate that animals lacking apoER2 express higher levels of brain APP, as well as both key amyloid peptides, while apoE levels are slightly lower. Following entorhinal cortex lesioning, apoE levels increase in the deafferented hippocampus, while a delay in the increase of APP was observed. Hippocampal amyloid levels are also increased in response to the lesion, and highly potentiated by the complete absence of apoER2 gene. The results suggest a significant role for apoER2 in signalling various proteins in response to massive deafferentation and may participate in maintaining efficient synaptic plasticity and dendritic remodelling.

Amyloid beta-Peptides↗
PubMed1998

Direct determination of dopamine D4 receptors in normal and schizophrenic postmortem brain tissue: a [3H]NGD-94-1 study.

Using an indirect subtraction binding technique and human postmortem tissue, several laboratories reported finding increases in dopamine D4 receptors in caudate nuclei of schizophrenic patients, although others have not replicated these findings. NGD-94-1 is a selective D4 antagonist with low affinity for the D2 and D3 receptors. [3H]NGD-94-1 has been used in this study to directly determine the density of D4 receptors in normals (n = 13) and schizophrenic subjects (n = 7) off antipsychotic drugs for at least 3 months prior to death, or on antipsychotic (n = 7) drugs at the time of death. Human postmortem coronal brain sections were incubated with [3H]NGD-94-1 and autoradiograms developed; and binding in pertinent regions was quantified. In normals, the highest density of [3H]NGD-94-1 binding was in the hippocampus (68 fmol mg(-1), temporal (33), insular (30), and entorhinal cortices (24.9). Significant increases in [3H]NGD-94-1 density in schizophrenics (n = 14) vs normals (n = 13) were observed in the entorhinal cortex (46%) at both low and high magnifications. The increases observed in the schizophrenics were found in both schizophrenics off antipsychotic drugs for at least 3 months prior to death and those on antipsychotic drugs at the time of death. Thus, the changes may be disease-related and not a consequence of pharmacological treatment. No significant differences were found between the two schizophrenic groups in any brain area studied.

Adult↗
PubMed2005

Hippocampal mechanisms for the context-dependent retrieval of episodes.

Behaviors ranging from delivering newspapers to waiting tables depend on remembering previous episodes to avoid incorrect repetition. Physiologically, this requires mechanisms for long-term storage and selective retrieval of episodes based on the time of occurrence, despite variable intervals and similarity of events in a familiar environment. Here, this process has been modeled based on the physiological properties of the hippocampal formation, including mechanisms for sustained activity in entorhinal cortex and theta rhythm oscillations in hippocampal subregions. The model simulates the context-sensitive firing properties of hippocampal neurons including trial-specific firing during spatial alternation and trial by trial changes in theta phase precession on a linear track. This activity is used to guide behavior, and lesions of the hippocampal network impair memory-guided behavior. The model links data at the cellular level to behavior at the systems level, describing a physiologically plausible mechanism for the brain to recall a given episode which occurred at a specific place and time.

Animals↗
PubMed2003

Altered corticotropin-releasing factor (CRF) receptor immunoreactivity in the gerbil hippocampal complex following spontaneous seizure.

Considerable attention has been focused on the role of corticotropin-releasing factor (CRF) in neuropsychiatric disorders and neurodegenerative diseases including epilepsy. Therefore, in the present study, we investigated the temporal and spatial alteration of CRF receptor in the gerbil hippocampal complex in order to characterize the possible changes and associations with different sequelae of spontaneous seizure in these animals. Thirty minutes postictal, a decline in CRF receptor immunoreactivity was observed in the granule cells and hilar neurons. In the subiculum, CRF receptor immunoreactivity was also significantly decreased at this time point. Twenty-four hours after seizure onset, the immunoreactivity in these regions recovered to the pre-seizure level. Moreover, 30 min after seizure in the entorhinal cortex, the density of CRF receptor immunoreactivity began to decrease, particularly in the layers II and III, compared to pre-seizure group. Nevertheless, 24h after seizure onset, CRF receptor immunodensity had recovered to its seizure-sensitive (SS) level. These results suggest that altered CRF receptor expression in the hippocampal complex may affect tissue excitability and seizure activity in SS gerbils.

Animals↗
PubMed1997

Glial reaction in the hippocampal formation is highly correlated with aging in human brain.

Glial fibrillary acidic protein (GFAP), a biochemical marker of astrocytes and glial reaction, was quantified by immunoblotting in different brain areas from 33 non-demented patients with a Mini Mental State Examination score above 26 and aged from 12 to 98 years. An increase of GFAP with age was first found in the hippocampus and then in the entorhinal cortex. In both regions, GFAP amounts were correlated with age (r = 0.768). In the isocortex, the increase of GFAP as a function of age was also significant (r = 0.672), but less than for the hippocampal region. GFAP levels increased dramatically after the age of 65 years, and more especially in the hippocampal formation. This glial reaction was observed in aged controls that do not show cognitive impairment and the neuropathological hallmarks of Alzheimer's disease.

Adolescent↗
PubMed1981

Localization of enkephalin-like immunoreactivity to identified axonal and neuronal populations of the rat hippocampus.

The distribution of enkephalin-like immunoreactivity in the hippocampal formation of the rat was analyzed. Two specific projection systems are described. The first emerges from the hilus of the dentate gyrus and appears to terminate with notably large boutons on the proximal apical and, to a lesser extent, basal dendrites of hippocampal regio inferior pyramidal cells. This projection corresponds in source, position, and character to the hippocampal mossy fiber system. The second axonal population enters the temporal hippocampal formation from the medial wall of the subicular complex and follows the hippocampal fissure to occupy stratum lacunosum-moleculare of the hippocampus proper and the distal third of the dentate gyrus molecular layer; this pattern corresponds to the distribution of afferent input from the lateral entorhinal cortex and/or perirhinal area. Lesions of the hilus or retrohippocampal area caused a selective depletion of immunoreactivity in the mossy fiber fields and molecular layers of the dentate gyrus, respectively. Enkephalin-like immunoreactivity was found within the somata of three types of hippocampal neurons: 1) granule cells of the dentate gyrus, 2) occasional pyramidal shaped cells of field CA1 stratum pyramidale, and 3) varied scattered interneurons. Of this last group, two types of interneurons were consistently seen. The first occupy the border between stratum radiatum and stratum lacunosum-moleculare and extend processes at right angles to the long axis of the pyramidal cell dentrites, whereas the second lie within stratum radiatum of field CA1 and extend processes in alignment with the long axis of the pyramidal cell dendrites. Cells containing enkephalin-like immunoreactivity were also observed in the subiculum and retrohippocampal region, most notably including layers II and III of the lateral entorhinal cortex-perirhinal area--the probable source of extrinsic immunoreactive input to the hippocampal formation. Intraventricular colchicine treatment intensified the immunoreactive staining of some hippocampal neurons but did not reveal any cell types not seen to be labeled in untreated rats.

Animals↗