Biomedical subjects

Laura Lee Colgin

Publications and source records attributed to Laura Lee Colgin.

9 recordsLinked to original sources

PubMed2005

Mechanisms of late-onset cognitive decline after early-life stress.

Progressive cognitive deficits that emerge with aging are a result of complex interactions of genetic and environmental factors. Whereas much has been learned about the genetic underpinnings of these disorders, the nature of "acquired" contributing factors, and the mechanisms by which they promote progressive learning and memory dysfunction, remain largely unknown. Here, we demonstrate that a period of early-life "psychological" stress causes late-onset, selective deterioration of both complex behavior and synaptic plasticity: two forms of memory involving the hippocampus, were severely but selectively impaired in middle-aged, but not young adult, rats exposed to fragmented maternal care during the early postnatal period. At the cellular level, disturbances to hippocampal long-term potentiation paralleled the behavioral changes and were accompanied by dendritic atrophy and mossy fiber expansion. These findings constitute the first evidence that a short period of stress early in life can lead to delayed, progressive impairments of synaptic and behavioral measures of hippocampal function, with potential implications to the basis of age-related cognitive disorders in humans.

Age Factors↗

PubMed2005

Blockade of NMDA receptors enhances spontaneous sharp waves in rat hippocampal slices.

An in vitro model of sharp waves (SPWs) and ripples was used to investigate the involvement of NMDA receptors in SPW/ripple production. Intracellular recordings from CA3 pyramidal cells confirmed that SPWs are composed of primarily excitatory currents. Unexpectedly, NMDA receptor antagonists greatly increased the size of SPWs and ripples. This effect may have involved decreased calcium influx through NMDA receptors and a subsequent reduction in the activation of SK2 calcium-activated potassium channels. The results support the claim that activation of NMDA receptors can serve to dampen the excitation of SPWs.

Animals↗

PubMed2004

Spontaneous waves in the dentate gyrus of slices from the ventral hippocampus.

Spontaneous negative-going potentials occurring at an average frequency of 0.7 Hz were recorded from the dentate gyrus of slices prepared from the temporal hippocampus of young adult rats. These events (here termed "dentate waves") in several respects resembled the dentate spikes described for freely moving rats during immobile behaviors and slow-wave sleep. Action potentials were observed on the descending portion of the in vitro waves and, as expected from this, whole cell recordings established that the waves were composed of depolarizing currents. Dentate waves appeared to be locally generated within the granule cell layer and were greatly reduced by antagonists of AMPA-type glutamate receptors or by lesions to the entorhinal cortex. Simultaneous recordings indicated that the waves were often synchronized in the inner and outer blades of the dentate gyrus. Knife cuts through the perforant path and the commissural/associational system did not eliminate synchronization, leaving electrotonic propagation via gap junctions as its probable cause. In accord with this, cuts that separated the two blades of the dentate eliminated synchronization between them, and a compound that inhibits gap junctions reduced wave activity. Dentate waves were regularly accompanied by sharp waves in field CA3 and were reduced in size by the acetylcholinesterase inhibitor, physostigmine. It is hypothesized that dentate waves occur when spontaneous glutamate release from dentate afferents produces action potentials in neighboring granule cells that then summate electrotonically into a population event; once initiated, the waves propagate, again electrotonically, and thereby engage a significant portion of the granule cell population.

Acetylcholine↗

PubMed2004

Long-term potentiation is impaired in rat hippocampal slices that produce spontaneous sharp waves.

Sharp waves (SPWs) occur in the hippocampal EEG during behaviours such as alert immobility and slow-wave sleep. Despite their widespread occurrence across brain regions and mammalian species, the functional importance of SPWs remains unknown. Experiments in the present study indicate that long-term potentiation (LTP) is significantly impaired in slices, prepared from the temporal aspect of rat hippocampus, that spontaneously generate SPW activity. This was probably not due to anatomical and/or biochemical abnormalities in temporal slices because stable LTP was uncovered in field CA1 when SPWs were eliminated by severing the projection from CA3. The same procedure did not alter LTP in slices lacking SPWs. Robust and stable LTP was obtained in the presence of SPWs in slices treated with an adenosine A1 receptor antagonist, a finding that links the present results to mechanisms related to the LTP reversal effect. In accord with this, single stimulation pulses delivered intermittently in a manner similar to the SPW pattern interfered with LTP to a similar degree as spontaneous SPWs. Taken together, these results suggest the possibility that SPWs in the hippocampus constitute a neural mechanism for forgetting.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2003

Septal modulation of excitatory transmission in hippocampus.

Application of the acetylcholinesterase inhibitor physostigmine to conventional hippocampal slices caused a significant reduction of field excitatory postsynaptic potentials (EPSPs) elicited by single pulse stimulation to the medial perforant path. Similar but smaller effects were obtained in the lateral perforant path and other excitatory pathways within hippocampus. The reductions were blocked by atropine, were not accompanied by evident changes in the EPSP waveform, and were eliminated by lesions to the cholinergic septo-hippocampal projections. Antidromic responses to mossy fiber stimulation, recorded in stratum granulosum, were not affected by the drug. However, paired-pulse facilitation was reliably increased, indicating that the depressed synaptic responses were secondary to reductions in transmitter release. The absence of cholinergic axo-axonic connections in the molecular layer suggests that physostigmine reduces presynaptic release by increasing retrograde signaling from the granule cells. In accord with this, an antagonist of the CB1 cannabinoid receptor eliminated the effects of physostigmine on synaptic responses, while an antagonist of the presynaptically located m2 muscarinic acetylcholine receptor did not. This is in contrast to previously reported effects involving application of cholinergic agonists, in which presynaptic inhibition likely results from direct activation of presynaptically located muscarinic receptors. In summary, it is proposed that the cholinergic inputs from the septum to the middle molecular layer modulate, via endocannabinoid release, the potency of the primary excitatory afferent of hippocampus.

Animals↗

PubMed2003

Cholinergic plasticity in the hippocampus.

Tests were made for use-dependent plasticity in the cholinergic projections to hippocampus. Transient infusion of the cholinergic agonist carbachol into hippocampal slices induced rhythmic activity that persisted for hours after washout. Comparable effects were obtained with physostigmine, a drug that blocks acetylcholine breakdown and thereby enhances cholinergic transmission. It thus seems that activation of cholinergic synapses induces lasting changes in hippocampal physiology. Two lines of evidence indicated that cholinergic synapses are also the sites at which the plasticity is expressed. First, the induction and expression of the rhythms were not blocked by the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovaleric acid, indicating that a long-term potentiation effect between pyramidal cells was not involved. Second, a muscarinic antagonist (atropine) completely abolished stable rhythmic activity after agonist washout. This result indicates that endogenous cholinergic activity is responsible for the persistence of rhythmic oscillations. These experiments suggest that short periods of intense cholinergic activity induce lasting changes in cholinergic synapses and thus extend such forms of plasticity to beyond the glutamatergic system.

2-Amino-5-phosphonovalerate↗

PubMed2003

Endogenous waves in hippocampal slices.

Sharp waves (SPWs) are thought to play a major role in intrinsic hippocampal operations during states in which subcortical and cortical inputs to hippocampus are reduced. This study describes evidence that such activity occurs spontaneously in appropriately prepared rat hippocampal slices. Irregular waves, with an average frequency of approximately 4 Hz, were recorded from field CA3 in slices prepared from the temporal region of hippocampus. The waves persisted for hours and were not accompanied by aberrant discharges. Multi-electrode analyses established that they were locally generated within each of the subfields of CA3 and yet were coherent between subfields. The sharp waves were reversibly blocked by either cholinergic or serotonergic stimulation. Various lines of evidence indicate that they are propagated by the CA3 associational system.

Animals↗

PubMed2002

Interactions between recording technique and AMPA receptor modulators.

Whole cell recording (EPSCs) and extracellular recording (field EPSPs) were compared in hippocampal field CA1 with regard to the effects of experimental treatments that increase AMPA receptor gated currents. Cyclothiazide, which maintains AMPA receptors in the sensitized state, caused a rapid and pronounced increase in EPSCs but only minor changes in field EPSPs. This difference was evident in recordings carried out at 22 and 32 degrees C and with different solutions in the clamp pipette. The larger effect of cyclothiazide on EPSCs was unaffected by blockade of GABA and NMDA receptors. Two-dimensional current source density analyses derived from 64 recording sites were used to provide extracellular estimates of AMPA receptor mediated synaptic currents. With this method, cyclothiazide again had much smaller effects than were obtained with whole cell clamp. Differences between whole cell and extracellular recordings were present, although not as pronounced, for the ampakines, a class of drugs that slow both deactivation and desensitization of AMPA receptors. Additionally, increases in synaptic responses produced by frequency facilitation, a manipulation that enhances the number of bound receptors, were not qualitatively different between recording techniques. These results support the conclusion that the whole cell clamp technique may alter AMPA receptors in such a way as to increase the relative importance of desensitization.

Animals↗

PubMed2002

Long-term potentiation alters the modulator pharmacology of AMPA-type glutamate receptors.

Changes in the biophysical properties of AMPA-type glutamate receptors have been proposed to mediate the expression of long-term potentiation (LTP). The present study tested if, as predicted from this hypothesis, AMPA receptor modulators differentially affect potentiated versus control synaptic currents. Whole cell recordings were collected from CA1 pyramidal neurons in hippocampal slices from adult rats. Within-neuron comparisons were made of the excitatory postsynaptic currents (EPSCs) elicited by two separate groups of Schaffer-collateral/commissural synapses. LTP was induced by theta burst stimulation in one set of inputs; cyclothiazide (CTZ), a drug that acts on the desensitization kinetics of AMPA receptors, was infused 30 min later. The decay time constants of the potentiated EPSCs prior to drug infusion were slightly, but significantly, shorter than those of control EPSCs. CTZ slowed the decay of the EPSCs, as reported in prior studies, and did so to a significantly greater degree in the potentiated synapses. Additionally, infusion of CTZ resulted in significantly greater effects on amplitude in potentiated pathways as compared with control pathways. The interaction between LTP and CTZ was also obtained in a separate set of experiments in which GABA receptor antagonists were used to block inhibitory postsynaptic currents. Additionally, there was no significant change in paired-pulse facilitation in the presence of CTZ, indicating that presynaptic effects of the drug were negligible. These findings provide new evidence that LTP modifies AMPA receptor kinetics. Candidates for the changes responsible for the observed effects of LTP were evaluated using a model of AMPA receptor kinetics; a simple increase in the channel opening rate provided the most satisfactory match with the LTP data.

6-Cyano-7-nitroquinoxaline-2,3-dione↗