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PubMed2004

Reversal and consolidation of activity-induced synaptic modifications.

Persistent activity-induced synaptic modification is generally regarded as the cellular basis for developmental refinement of neuronal connections and for learning and memory. It has long been recognized that synaptic modifications can be reversed by subsequent stimuli. Recent in vivo studies indicate that reversal of synaptic modifications is a natural process that can be triggered by physiological activity. Long-term potentiation (LTP) of hippocampal synapses in adult rats was reversed as rats entered a novel environment. LTP of retinotectal synapses in developing Xenopus was also reversed by subsequent spontaneous activity. Repetitive stimulation with spaced patterns, however, can overcome this reversal, leading to stabilized synaptic modifications. The requirement of spaced stimulus patterns for stable synaptic modifications could ensure appropriate refinement of developing connections.

Animals↗

PubMed2006

Weak, physiologically patterned magnetic fields do not affect maze performance in normal rats, but disrupt seized rats normalized with ketamine: possible support for a neuromatrix concept?

The concept of a neuromatrix as a determinant of behavior proposes that complex neuroelectromagnetic patterns supported by specific spatial configurations of neurons underlie the generation of behaviors. When the pattern of neuronal connectivity is changed, as occurs during limbic epilepsy, neuroelectromagnetic patterns change in parallel to sustain behavioral output. Thus, a testable prediction of the neuromatrix concept is that the "normal" behaviors of animals with markedly reorganized neuroelectromagnetic patterns are vulnerable to specific stimuli that are ineffective when applied to a normal population. Because rats treated with ketamine after being induced to seize with pilocarpine exhibit behaviors indistinguishable from those of control populations despite marked changes in brain structure, they represent an ideal population in which to examine this hypothesis. Ketamine-treated pilocarpine-seized rats and normal rats were exposed continuously either to a complex sequence magnetic field or to control conditions during the acquisition of a radial arm maze task for 8 consecutive days. After 14 days of subsequent exposure to a frequency-modulated field (7-500 nT), during which time there was no training, the rats that had been induced to seize and had been exposed continuously to this magnetic configuration exhibited conspicuously slower response durations per arm than rats that had been induced to seize and exposed to control conditions or normal rats that had been exposed to either magnetic fields or control conditions. Thus, the behaviors of rats who have sustained multiple, discrete injuries throughout the brain may be seriously disrupted by the appropriate pattern of exogenous weak magnetic fields. Our results represent the first empirical support for the concept of the neuromatrix.

Analgesics↗

PubMed2002

The effects of chronic ethanol consumption on neurotrophins and their receptors in the rat hippocampus and basal forebrain.

Damage to the basal forebrain frequently results in deficits in learning and memory. Mnenonic dysfunction also occurs following prolonged ethanol consumption in humans and in animal models of chronic ethanol intake, accompanied by specific abnormalities in synaptic transmission between the basal forebrain and hippocampus. The integrity of at least some of the reciprocal neuronal connections between these brain regions is influenced by target-derived neurotrophic factors. We used a semiquantitative reverse transcription polymerase chain reaction technique to measure the messenger RNA for neurotrophins BDNF and NGF, and for their receptors trkB, trkA, and the low affinity receptor, p75(NTR) in the hippocampus and basal forebrain of rats after 28 weeks of alcohol consumption without malnutrition. This chronic ethanol treatment (CET) resulted in a marked and selective reduction in basal forebrain trkA mRNA. Western blotting revealed a similar reduction of basal forebrain trkA protein. CET effects on basal forebrain trkA may reflect impaired NGF signaling that could compromise septohippocampal synaptic connections, cholinergic differentiation, and emergent functional abilities dependent on these properties.

Alcohol Drinking↗

PubMed1994

An N-methyl-D-aspartate receptor antagonist does not prevent eye-specific segregation in the ferret retinogeniculate pathway.

Recent studies have shown that electrical activity, particularly that mediated by NMDA receptors, has a profound effect on the development of specific neuronal connections. Blocking NMDA receptors in the ferret's lateral geniculate nucleus prevents the segregation of retinal afferents into ON and OFF sublaminae. We have now examined the involvement of NMDA receptors in the separation of afferents from the two eyes that occurs in the lateral geniculate nucleus several weeks earlier in development. Blockade of NMDA receptor activity does not appear to interfere with this eye-specific segregation.

Animals↗

PubMed1998

Hippocampal NMDA receptor mRNA undergoes subunit specific changes during developmental lead exposure.

The N-methyl-D-aspartate (NMDA) receptor has shown to play an important role in the cognitive deficits associated with developmental lead (Pb) exposure. In this study, we examined the effects of low-level Pb exposure on NMDA receptor subunit gene expression in the developing rat brain. The pattern of NR1, NR2A, NR2B, and NR2C subunit mRNA in situ hybridization was consistent with previous studies. Brain levels of NR1 and NR2A mRNAs were lowest shortly after birth, increasing to reach peak levels by 14 or 21 days of age and subsequently decreasing at 28 days of age. NR2B mRNA levels were highest during early development and decreased as the animals aged. NR2C subunit mRNA was restricted to the cerebellum and a signal was not detectable until the second week of life. Lead exposure resulted in significant and opposite effects in NR1 and NR2A subunit mRNA expression with no changes in NR2B or NR2C subunit expression. The Pb-induced changes in NR1 and NR2A subunit mRNA were mainly present in the hippocampus. Hippocampal NR1 mRNA levels were significantly increased in the CA1 (15.3%) and CA4 (26.8%) pyramidal cells from 14-day-old Pb-exposed rats. At 21 days of age, only the NR1 mRNA at the CA4 subfield remained significantly elevated (10.3%). Lead exposure caused reductions of NR2A mRNA levels (11.9-19.3%) in the pyramidal and granule cell layers of the hippocampus at 14 and 21 days of age. NR1 mRNA levels were also significantly increased (14.0%) in the cerebellum of 28-day-old rats with no change in NR2A mRNA at any age. No significant changes in subunit mRNA levels were present in cortical or subcortical regions at any age. The Pb-induced changes in hippocampal NMDA receptor subunit mRNA expression measured in the present study may lead to modifications in receptor levels or subtypes and alter the development of defined neuronal connections which require NMDA receptor activation.

Animals↗

PubMed1998

Downregulation of oxidative phosphorylation in Alzheimer disease: loss of cytochrome oxidase subunit mRNA in the hippocampus and entorhinal cortex.

Messenger RNA (mRNA) for cytochrome oxidase subunit II (COX II) was localized by in situ hybridization in the entorhinal cortex and hippocampal formation of postmortem brain tissue from normal human subjects and from patients with Alzheimer disease (AD). In the control entorhinal cortex, COX II mRNA was detected mainly in neuronal cell bodies of layers II and IV. In control hippocampal formation, highest levels were localized in neuronal cell bodies of the dentate gyrus and the CA3 and CA1 regions, neurons that are involved in the major input and output pathways of the hippocampal formation. In AD brain, COX II mRNA was markedly reduced in the entorhinal cortex and the hippocampal formation compared with control brain. In the AD hippocampal formation, reductions were in regions severely affected by AD pathology as well as in regions that were relatively spared. These results are consistent with the hypothesis that reduced mitochondrial energy metabolism reflects loss of neuronal connections in AD.

Aged↗

PubMed1995

The neuronal intermediate filament, alpha-internexin is transiently expressed in amacrine cells in the developing mouse retina.

We have investigated the expression of intermediate filament proteins in the developing mouse retina by immunohistochemistry. Antibodies against alpha-internexin, the three neurofilament subunits (NF-L, NF-M, NF-H), vimentin, and glial fibrillary acidic protein (GFAP) were used to determine the relative expression of these proteins at different post-natal stages of mouse retinal development. alpha-Internexin is widely distributed in the process of amacrine cells, horizontal cells and retinal ganglion cells before post-natal day 5 (P5). At this age, NF-L and NF-M are detected primarily in the processes of horizontal cells and retinal ganglion cells, but are rarely found in amacrine cell processes. After P5, alpha-internexin is found to colocalize with other neuronal intermediate filaments in the cell processes of horizontal and ganglion cells, but its expression is barely detectable in amacrine cells processes. NF-H is not encountered in either the horizontal cell processes or the ganglion nerve fibers until P5. Vimentin is present in all glial cells (astrocytes and Müller cells) and some horizontal cell processes during development, while GFAP is found only in astrocyte processes of the mature retina. The transient presence of alpha-internexin in amacrine cells only in early development suggests that the protein may play a role in the plasticity of neuronal connections in the retina.

Animals↗

PubMed1992

Detubularization-induced contractile response change of the ileum following ileocystoplasty.

We reported previously that following ileocystoplasty the structure and pharmacologic response of the implanted ileum changes towards that of the bladder. Specifically, the relaxation response to alpha adrenergic (methoxamine) and purinergic (ATP) stimulation reverses to a contractile response one month after the ileal segment is surgically made part of the urinary bladder. The present study was designed to investigate possible signals for this change and also to determine whether bladder responses would mimic the ileum if surgically interposed into the ileal stream. Rabbits in group 1 underwent bladder interposition into the functioning terminal ileum, rabbits in group 2 underwent tubularized ileocystoplasty and rabbits in group 3 underwent detubularized ileocystoplasty with urinary diversion. Twelve rabbits survived and were available for evaluation; five in group 1, three in group 2 and four in group 3. Analysis was done six weeks after surgery. In group 1 animals, the interposed bladder showed epithelial changes towards ileum and also a change in its in-vitro contractile responses towards that of ileum. In group 2 animals the tubular cystoplastic ileum showed minimal functional and morphologic changes. In group 3 animals, the defunctionalized, detubular cystoplastic ileum showed alpha adrenergic and purinergic response changes towards bladder. These results indicate that detubularization with interruption in the arrangement of smooth muscle fibers as well as the breach in the integrity of neuronal connections is likely to be the primary signal for the change in the ileum towards bladder induced by cystoplasty. The results can not rule out reinnervation of the intestinal segment by bladder nerves. In addition these data demonstrate that the pharmacologic response of the bladder changes towards the ileum within six weeks after the bladder is surgically made part of the ileum.

Adenosine Triphosphate↗

PubMed2002

Involvement of adrenoceptors in the angiotensin II-induced expression of inducible transcription factors in the rat forebrain and hypothalamus.

Angiotensin II (Ang II) acts as a neuromodulator/neurotransmitter in specific brain nuclei involved in the regulation of blood pressure and volume homeostasis. It also induces a highly differentiated transcription factor expression in these nuclei. We investigated whether adrenoceptors, which modulate other central actions of angiotensin II like the vasopressin release, also play a role in the AT1 receptor-mediated expression of the transcription factors (TF) c-Fos, c-Jun and Krox-24 in the rat brain. Ang II, injected intracerebroventricularly, induced the expression of c-Fos, c-Jun and Krox-24 in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Pretreatment with the alpha 1-adrenoceptor antagonist, prazosin, significantly inhibited the Ang II-induced transcription factor expression in the SON and PVN. The alpha 2-adrenoceptor antagonist, yohimbine, also reduced Ang II-stimulated transcription factors significantly in both nuclei. This inhibition was mainly localized in vasopressinergic magnocellular neurons in both nuclei. The beta-adrenoceptor antagonist, propranolol, did not influence the Ang II-induced expression of TF. Our results show that both, Ang II-induced vasopressin release and transcription factor expression, involve the same neuronal connections in the brain, implicating that the signal transduction pathways leading to the two different effects are at least to a certain degree convergent.

Angiotensin II↗

PubMed2002

Chronic antidepressant treatment increases the membrane expression of AMPA receptors in rat hippocampus.

It has been proposed that potentiation of AMPA receptor (AMPAR) function may be useful in the treatment of depression. Here we studied the acute and chronic effect of the antidepressants desipramine and paroxetine, which differentially affect monoamine reuptake, on the expression of the AMPAR subunits GluR1 and GluR2/3, analyzed by Western blot, both in total and in membrane-enriched extracts from rat hippocampus. Acute antidepressant treatment did not produce any change in the expression of AMPAR subunits. In chronic treatments, rats were daily treated with the antidepressants (10 mg/kg/day) for 7, 14, or 21 days. In rats receiving either of the two antidepressant treatments for 21 consecutive days and killed 24 h after the last injection, an increase in GluR1 and GluR2/3 levels was found in the membrane fraction, with no significant change in the total extract, suggesting a trafficking of the AMPAR subunits from intracellular pools to synaptic sites in the hippocampus. This appeared to be a region-specific effect since no change in AMPAR subunit expression was found in the frontal cortex. Previously reported modifications in phosphorylating enzymes by chronic antidepressants could perhaps play a role in hippocampal membrane insertion of AMPAR subunits. When the survival time after the 21-day-treatment was longer - 72 instead of 24 h - the hippocampal membrane expression of GluR1, but not of GluR2/3 subunits, was still increased, as could be expected from the distinct mechanisms operating in synaptic delivery of GluR1 and GluR2/3 subunits. The antidepressant-induced increase in the number of GluR1- and GluR2/3-containing AMPARs at the synapses may indicate an enhanced AMPAR-mediated synaptic transmission which could help to counteract the alterations in neuronal connectivity which appear to underlie the pathophysiology of mood disorders.

Animals↗

PubMed2000

Human development of perceptual organization.

Two relevant dimensions are revealed within which developmental patterns of perceptual organization might be investigated. Within the local-integrative dimension, employing a contour integration task, we found indications that spatial integration develops slowly. We also found reduced contextual modulation of a local target in children employing the Ebbinghaus illusion. Within the action-perception dimension, we hypothesize a relatively slow development of the perceptual system (mediated by the ventral visual stream), as compared to the development of the action system (mediated by the dorsal visual stream). Taken together, the data indicate that long-range neuronal connectivity supporting perceptual organization in the posterior pole of the brain, and in the ventral visual pathway is not fully developed in young children.

Adolescent↗

PubMed2003

Cell adhesion molecules during inner ear and hair cell development, including notch and its ligands.

Cellular adhesion plays a key role in a number of unique developmental events, including proliferation, cell fate, morphogenesis, neurite outgrowth, fasciculation, and synaptogensis. The number of families of molecules that can mediate cell adhesion and the number of members of each of those families has continued to increase over time. Moreover, the potential for the formation of different pairs of heterodimers with different binding specificities, and for both homo- and hetero-dimeric interactions suggest that a vast number of specific signaling events can be mediated through the expression of different combinations of adhesion factors at different developmental time points. By comparison with the number of known adhesion molecules and their potential effects, our understanding of the role of adhesion in ear development is extremely limited. The patterns of expression for some adhesion molecules have been determined for some aspects of inner ear development. Similarly, with a few exceptions, functional data to indicate the roles of these adhesion molecules are also lacking. However, a consideration of even the limited existing data must lead to the conclusion that adhesion molecules play key roles in all aspects of the development of the auditory system. Unique expression domains for different groups of adhesion molecules within the developing otocyst and ear strongly suggest a role in the determination of different cellular domains. Similarly, the specific expression of adhesion molecules on developing neurites and their target hair cells, suggests a key role for adhesion in the establishment of neuronal connections and possible the development of tonotopy. Finally, the recent demonstration that Cdh23 and Pcdh15 play specific roles in the formation of the hair cell stereociliary bundle provides compelling evidence for the importance of adhesion molecules in the development of stereocilia. With the imminent completion of the mouse genome, it seems likely that the number of adhesion molecules can soon be fixed and that it will then be possible to generate a more comprehensive map of expression of these molecules within the developing inner ear. At the same time, the generation of new transgenic and molecular technologies promises to provide researchers with new tools to examine the specific effects of different adhesion molecules during inner ear development.

Animals↗

PubMed1999

A striking organization of a large family of human neural cadherin-like cell adhesion genes.

We have identified 52 novel human cadherin-like genes organized into three closely linked clusters. Comparison of the genomic DNA sequences with those of representative cDNAs reveals a striking genomic organization similar to that of immunoglobulin and T cell receptor gene clusters. The N-terminal extracellular and transmembrane domains of each cadherin protein are encoded by a distinct and unusually large exon. These exons are organized in a tandem array. By contrast, the C-terminal cytoplasmic domain of each protein is identical and is encoded by three small exons located downstream from the cluster of N-terminal exons. This unusual organization has interesting implications regarding the molecular code required to establish complex networks of neuronal connections in the brain and the mechanisms of cell-specific cadherin-like gene expression.

Amino Acid Sequence↗

PubMed2000

Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity.

A Drosophila homolog of human Down syndrome cell adhesion molecule (DSCAM), an immunoglobulin superfamily member, was isolated by its affinity to Dock, an SH3/SH2 adaptor protein required for axon guidance. Dscam binds directly to both Dock's SH2 and SH3 domains. Genetic studies revealed that Dscam, Dock and Pak, a serine/threonine kinase, act together to direct pathfinding of Bolwig's nerve, containing a subclass of sensory axons, to an intermediate target in the embryo. Dscam also is required for the formation of axon pathways in the embryonic central nervous system. cDNA and genomic analyses reveal the existence of multiple forms of Dscam with a conserved architecture containing variable Ig and transmembrane domains. Alternative splicing can potentially generate more than 38,000 Dscam isoforms. This molecular diversity may contribute to the specificity of neuronal connectivity.

Amino Acid Sequence↗

PubMed1998

Molecular mechanisms of neurotropic herpesvirus invasion and spread in the CNS.

Pseudorabies virus (PRV) is a herpesvirus in the subfamily alphaherpesvirinae (the alpha herpesviruses). After primary infection at mucosal surfaces, PRV infects the peripheral nervous system in its natural host (swine) with occasional invasion of the central nervous system. When other hosts (including cows and rodents) are infected, the infection almost always gives rise to fatal disease in the CNS as a result of infection of peripheral neurons and subsequent spread to the brain. Part of the ability to cause fatal CNS disease can be attributed to a viral glycoprotein called gE. Viruses lacking gE are thought to be less virulent because they do not spread efficiently from cell to cell. Based on a set of gE mutations we have constructed, we suggest that these two phenotypes of cell-cell spread and virulence reflect separate functions of the gE protein. In this report, we show that viruses carrying these new gE mutations have marked reduction in virulence, yet spread efficiently in defined neural circuits in the rat brain. As such, they offer new insight and opportunities for understanding of viral disease and host response to injury, as well as in the construction of viral tracers of neuronal connections.

Animals↗

PubMed2003

Precise placement of multiple electrodes into functionally predefined cortical locations.

Current research on topics such as effective connectivity, neuronal coding strategy or signal propagation in the central nervous system requires simultaneous recordings from multiple sites within functionally grouped but topologically distributed neuronal clusters. We have addressed this issue by characterization of the cortical functional architecture using optical imaging of intrinsic signals (OI) and subsequent placement of multiple, individually adjustable electrodes into pre-selected domains. In order to achieve maximum precision and flexibility for the positioning of electrodes, a plastic cylinder containing channels of an extremely high aspect ratio (density >20 channels/mm(2)) was fixed above the cortex and individual channel positions were superimposed onto the functional maps of orientation columns obtained previously with OI. Subsequently, channels corresponding to the desired locations in the functional map were used as guide tubes for electrode insertion. The spatial precision of this approach was in the range of 100 microm and experiments in cat primary visual cortex revealed a close correlation between the desired and the actually recorded orientation preferences of the targeted columns. The method is applicable to all cortical areas in which OI is feasible and offers a high degree of flexibility with respect to the number and geometry of applicable probes. It is, thus, an excellent tool for studying distributed codes and interactions between multiple predefined recording sites.

Animals↗

PubMed1997

'Semifree-floating' treatment: a simple and fast method to process consecutive sections for immunohistochemistry and neuronal tracing.

A method is described which allows for histochemical processing of thick (50-200 microm) and consecutive sections of neural tissue, a prerequisite for many neuroanatomical studies. Two examples are given: (A) biotin-dextran-amine (BDA) tracing of neuronal connections in 50-100 microm thick vibratome sections of the adult rat brain and (B) immunohistochemical analysis of tyrosine hydroxylase-positive bulbospinal fibers in 50 microm thick cryosections of spinal cord.

Animals↗

PubMed2000

Postnatal developmental changes in AMPA and NMDA receptors in the rat vestibular nuclei.

Changes in the expression of the AMPA receptor subunits GluR1-4 and of the NMDA receptor subunits NR1, NR2A-D were investigated in the developing rat medial and lateral vestibular nuclei. Analyses were performed using nonradioactive in situ hybridization and immunoblotting with subunit-specific antibodies. During the postnatal development, glutamatergic receptor subunits were differentially expressed in the vestibular nuclei. The level of expression of GluR1, GluR4 and NR1 subunits was higher in the developing brain as compared to the adult. We observed a gradual increase in GluR2/3, NR2A, NR2B and NR2C levels of expression in the medial and lateral vestibular nuclei during the first 3 weeks of postnatal development. In situ hybridization results were consistent with immunoblot analyses. The differential expression of AMPA and NMDA receptor subunits in immature vestibular neurons is consistent with changes in glutamate receptor properties. This may be related to the postsynaptic regulation of receptor subunits associated with the synaptic plasticity of the vestibular neuron connections during specific sequences of postnatal development.

Animals↗