Biomedical subjects

L S Krimer

Publications and source records attributed to L S Krimer.

14 recordsLinked to original sources

PubMed2006

Electrophysiological differences between neurogliaform cells from monkey and rat prefrontal cortex.

Current dogma holds that a canonical cortical circuit is formed by cellular elements that are basically identical across species. However, detailed and direct comparisons between species of specific elements of this circuit are limited in number. In this study, we compared the morphological and physiological properties of neurogliaform (NGF) inhibitory neurons in the prefrontal cortex (PFC) of macaque monkeys and rats. In both species, NGF cells were readily identified based on their distinctive morphological features. Indeed, monkey NGF cells had only a few morphological features that differed from rat, including a larger soma, a greater number of dendrites, and a more compact axonal field. In contrast, whole cell recordings of the responses to injected current steps revealed important differences between monkey and rat NGF cells. Monkey NGF cells consistently generated a short-latency first spike riding on an initial depolarizing hump, whereas in rat NGF cells, the first spike appeared after a substantial delay riding on a depolarizing ramp not seen in monkey NGF cells. Thus although rat NGF cells are traditionally classified as late-spiking cells, monkey NGF cells did not meet this physiological criterion. In addition, NGF cells in monkey appeared to be more excitable than those in rat because they displayed a higher input resistance, a lower spike threshold, and a higher firing frequency. Finally, NGF cells in monkey showed a more prominent spike-frequency adaptation as compared with rat. Our findings indicate that the canonical cortical circuit differs in at least some aspects of its constituent elements across species.

Action Potentials↗

PubMed2005

Properties of excitatory synaptic responses in fast-spiking interneurons and pyramidal cells from monkey and rat prefrontal cortex.

In the prefrontal cortex (PFC) during working memory tasks fast-spiking (FS) interneurons might shape the spatial selectivity of pyramidal cell firing. In order to provide time control of pyramidal cell activity, incoming excitatory inputs should excite FS interneurons more vigorously than pyramidal cells. This can be achieved if subthreshold excitatory responses of interneurons are considerably stronger and faster than those in pyramidal neurons. Here we compared the functional properties of excitatory post-synaptic potentials (EPSPs) between pyramidal cells and FS interneurons in slices from monkey dorsolateral PFC and rat prelimbic cortex. Miniature, unitary (in connected pairs or by minimal stimulation) and compound (evoked by electrical stimulation of the white matter) EPSPs were recorded in whole cell mode. We found that EPSPs were significantly larger and faster in FS interneurons than those recorded from pyramidal cells, consistent with the idea of more efficient recruitment of FS interneurons compared to pyramidal neurons. Similar results were obtained in monkey and rat PFC, suggesting a stable role of FS interneurons in this circuitry across species.

Action Potentials↗

PubMed2004

Localization of calcium-binding proteins in physiologically and morphologically characterized interneurons of monkey dorsolateral prefrontal cortex.

In the primate neocortex, little is known about the possible associations between functional subclasses of GABA neurons, their morphological properties and calcium-binding protein (CaBP) content. We used whole-cell current clamp recordings, combined with intracellular labeling and fluorescence immunohistochemistry, to determine these relationships for interneurons in layers 2-3 of monkey prefrontal cortex (PFC). Eighty-one interneurons were included in the analysis. Thirty-eight of these cells showed immunoreactivity for one of the three CaBPs tested. Co-localization of more than one CaBP was not observed in any of the interneurons examined. Interneurons with different CaBPs formed distinct populations with specific physiological membrane properties and morphological features. Parvalbumin (PV)-positive cells had the physiological properties characteristic of fast-spiking interneurons (FS) and the morphology of basket or chandelier neurons. Most calretinin (CR)-containing cells had the physiological properties ascribed to non-fast-spiking cells (non-FS) and a vertically oriented axonal morphology, similar to that of double bouquet cells. Calbindin (CB)-positive interneurons also had non-FS properties and included cells with double bouquet morphology or with a characteristic dense web of axonal collaterals in layer 1. Classification of the interneurons based on cluster analysis of multiple electrophysiological properties suggested the existence of at least two distinct groups of interneurons. The first group contained mainly PV-positive FS cells and the second group consisted predominantly of CR- and CB-positive non-FS interneurons. These findings may help to illuminate the functional roles of different groups of interneurons in primate PFC circuitry.

Action Potentials↗

PubMed2002

Dopamine modulation of neuronal function in the monkey prefrontal cortex.

We developed a brain slice preparation that allowed us to apply whole-cell recordings to examine the electrophysiological properties of identified synapses, neurons, and local circuits in the dorsolateral prefrontal cortex (DLPFC) of macaque monkeys. In this article, we summarize the results from some of our recent and current in vitro studies in the DLPFC with special emphasis on the modulatory effects of dopamine (DA) receptor activation on pyramidal and nonpyramidal cell function in superficial layers in DLPFC areas 46 and 9.

Animals↗

PubMed2001

A quantitative immunohistochemical study of astrocytes in the entorhinal cortex in schizophrenia, bipolar disorder and major depression: absence of significant astrocytosis.

A number of macroscopic changes have been reported in the temporal lobe in schizophrenia. We have evaluated the density of glial fibrillary acidic protein (GFAP)-positive astrocytes in cortical layers 2 through 6 in the intermediate subarea of entorhinal cortex in two cohorts: the first, 15 cases, made up of schizophrenic (n = 7) and normal nonpsychiatric control subjects (n = 8), and the second, 56 cases, composed of schizophrenic (n = 14), bipolar disorder (n = 13), major depressive (n = 14) and normal control subjects (n = 15). No significant difference in density of GFAP-positive astrocytes was detected between the psychiatric diagnostic groups and the normal controls in either of the two cohorts. In both cohorts there was a positive correlation between increasing age and astrocytic density which reached statistical significance in only the larger cohort (r = 0.38, p = 0.004). Our results find no evidence for astrocytosis in the entorhinal cortex in several mental illnesses. Although other studies have reported macroscopic and other structural abnormalities in this region, we have not detected astrocytic proliferation, which is a typical hallmark of atrophy and/or progressive neuronal loss.

Adult↗

PubMed2001

Prefrontal microcircuits: membrane properties and excitatory input of local, medium, and wide arbor interneurons.

To elucidate cortical mechanisms involved in higher cortical functions such as working memory, we have examined feedforward excitation transmitted by identified pyramidal cells to interneurons with predominantly horizontal axonal arbors, using dual somatic recordings in prefrontal cortical slices. Interneurons with local (narrow) axonal arbors, especially chandelier interneurons, exhibited extremely narrow action potentials and high evoked firing rates, whereas neurons identified with wide arbor axons generated wider spikes and lower evoked firing rates with considerable spike adaptation, resembling that of pyramidal cells. Full reconstruction of differentially labeled neuronal pairs revealed that local arbor cells generally received a single but functionally reliable putative synaptic input from the identified pyramidal neuron member of the pair. In contrast, more synapses (two to five) were necessary to depolarize medium and wide arbor neurons reliably. The number of putative synapses and the amplitude of the postsynaptic response were remarkably highly correlated within each class of local, medium, and wide arbor interneurons (r = 0.88, 0.95, and 0.99, respectively). Similarly strong correlations within these subgroups were also present between the number of putative synapses and variance in the EPSP amplitudes, supporting the validity of our morphological analysis. We conclude that interneurons varying in the span of their axonal arbors and hence in the potential regulation of different numbers of cortical modules differ also in their excitatory synaptic input and physiological properties. These findings provide insight into the circuit basis of lateral inhibition and functional interactions within and between cortical columns in the cerebral cortex.

Action Potentials↗

PubMed2001

Presynaptic regulation of recurrent excitation by D1 receptors in prefrontal circuits.

The prefrontal cortex plays a fundamental role in the working memory functions of the cerebral cortex and is also the site of dysfunction in several neurological and psychiatric disorders, including schizophrenia. Prefrontal neurons are distinguished by their capacity for sustained activity during the time a stimulus is held in memory, and this mnemonic response is considered a substrate for a variety of cognitive functions. The neuronal basis for sustained activity in prefrontal neurons is unknown but is thought to involve recurrent excitation among pyramidal neurons. Recent studies in awake behaving monkeys have demonstrated that the persistent activity in prefrontal neurons is modulated by dopamine. To examine the mechanisms by which dopamine might modulate transmission in local excitatory circuits, we have performed dual whole-cell recordings in connected pyramidal cell pairs with and without dopamine application. We find that dopamine reduces the efficacy of unitary excitatory neurotransmission in layer V pyramidal cells by decreasing its reliability. These effects, which are reproduced by a selective D1 agonist and blocked by a D1 antagonist, are independent of voltage changes and are not attenuated by blockade of sodium and potassium channels in the postsynaptic neurons. We conclude that attenuation of local horizontal excitatory synaptic transmission in layer V pyramidal neurons by dopamine is through D1 actions at a presynaptic site.

Animals↗

PubMed2000

Differential postnatal development of catecholamine and serotonin inputs to identified neurons in prefrontal cortex of rhesus monkey.

The monoaminergic innervation of cerebral cortex has long been implicated in its development. Methods now exist to examine catecholamine and serotonin inputs to identified neurons in the cerebral cortex. We have quantified such inputs on pyramidal and nonpyramidal cells in prefrontal cortex of rhesus monkeys ranging in age from 2 weeks to 10 years. Individual layer III neurons were filled with Lucifer yellow and double-immunostained with axons containing either tyrosine hydroxylase (TH) or 5-hydroxytryptamine (5-HT). The filled cells were reconstructed, and putative appositions between the axons and dendritic spines and shafts were quantified at high magnification using light microscopy. The density of catecholamine appositions on pyramidal neurons matures slowly, reaching only half the adult level by 6 months of age and thereafter rising gradually to adult levels by 2 years of age. By contrast, the density of serotonin appositions on pyramidal cells reaches the adult level before the second week after birth. The average adult pyramidal neuron in layer III of area 9m receives three times stronger input from catecholaminergic than from serotoninergic axons. The overall density of both inputs to interneurons does not appear to change during postnatal development. Selective changes in the TH innervation of pyramidal cells against a backdrop of constant TH innervation of interneurons suggest that the balance between excitation and inhibition may change developmentally in the prefrontal cortex. By contrast, 5-HT innervation of both types of neurons remains relatively constant over the age range studied.

Aging↗

PubMed1998

Dopaminergic regulation of cerebral cortical microcirculation.

Functional variations in cerebral cortical activity are accompanied by local changes in blood flow, but the mechanisms underlying this physiological coupling are not well understood. Here we report that dopamine, a neurotransmitter normally associated with neuromodulatory actions, may directly affect local cortical blood flow. Using light and electron-microscopic immunocytochemistry, we show that dopaminergic axons innervate the intraparenchymal microvessels. We also provide evidence in an in vitro slice preparation that dopamine produces vasomotor responses in the cortical vasculature. These anatomical and physiological observations reveal a previously unknown source of regulation of the microvasculature by dopamine. The findings may be relevant to the mechanisms underlying changes in blood flow observed in circulatory and neuropsychiatric disorders.

Animals↗

PubMed1997

Quantitative three-dimensional analysis of the catecholaminergic innervation of identified neurons in the macaque prefrontal cortex.

The present study provides a complete quantitative three-dimensional analysis of neurons in primate prefrontal cortex targeted by catecholaminergic axons. Individual pyramidal and nonpyramidal cells in fixed slices were filled with Lucifer yellow (LY) and recovered with anti-LY antibody combined with anti-tyrosine hydroxylase (TH) antisera to reveal catecholaminergic axons. The total number of TH contacts and TH apposition density (THAD) was obtained for pyramidal and nonpyramidal cells in different layers. Four TH contacts (two on spines and two on shafts) were selected for correlated electron microscopic examination and serially sectioned; all four were confirmed as membrane appositions. Quantitative analysis revealed 90 TH contacts per pyramidal neuron in layer III, with a density of 0.8 per 100 microm of dendritic length (i.e., averaging one contact per basal dendrite). Remarkably, pyramids of layers III, V, and VI had the same THAD values, with a highly regular distribution of TH terminals on their spiny dendritic trees. In contrast, TH contacts on nonpyramidal neurons in layer III were half as dense and, moreover, were distributed irregularly and showed large variation from cell to cell. Neurons in layers II and superficial III had the highest THAD, as compared with deeper layers (1.4 vs 0.7 per 100 micron of dendritic length for pyramids; 0.53 vs 0.4 for interneurons). The highly organized TH innervation of pyramidal neurons, with at least one contact on virtually every dendrite, indicates that catecholaminergic, presumably dopaminergic, terminals are placed strategically along the entire dendritic tree to modulate most, if not all, of the excitatory input of a neuron. At the same time, the sparsity of contacts per dendrite may explain cortical vulnerability in diseases involving dopamine.

Animals↗

PubMed1997

An interface holding chamber for anatomical and physiological studies of living brain slices.

The popularity of infrared DIC videomicroscopy for a variety of anatomical and physiological studies in living brain slices has created a need for holding chambers to allow more than one slice to be examined during a single experiment. As is well known, the yield of experiments requiring living brain slices is severely limited by the conditions under which these slices are maintained prior to being examined. Previous electrophysiological and morphological studies have demonstrated that slices maintained submerged in solution deteriorate dramatically compared to those kept at the gas/fluid interface, even after only 1.5 hours and many recording chambers incorporate the interface principle in their design. However, to our knowledge, as obvious as it may seem, this principle has not been applied to the design of holding chambers, and those which are in current use are of the non-optimal, submerged type. We have designed a simple, but extremely effective holding chamber for incubation of brain slices floating at the gas-fluid interface. The slices held in this chamber have been maintained for at least 12 hours in excellent condition as shown here by rich labeling of their local axonal arbors. In addition, the chamber is designed to hold individual slices (up to 1 cm2 in size) in separate compartments for better preservation of brain slices from valuable species (e.g. animals subjected to experimental treatments, nonhuman primates and human biopsy tissue).

Animals↗

PubMed1997

The entorhinal cortex: an examination of cyto- and myeloarchitectonic organization in humans.

The entorhinal cortex (ERC) has been implicated in the pathophysiology of Alzheimer's disease, schizophrenia and other disorders affecting cognitive functions. While powerful anatomical and histochemical methods (immunohistochemistry, in situ hybridization, etc.) may be applied (although with limitations) to postmortem human brain, each analysis should utilize a cytoarchitectonic approach to provide appropriate comparisons within the subdivisions of the ERC. Accordingly, we describe here the normal cyto- and myeloarchitecture of the human ERC as a prerequisite for the accompanying study of this region in schizophrenia. Our parcellation of this cortex differs from previous treatments in three ways. First, we adopted specific criteria of inclusion to define each subdivision of the region. Although distinctive ERC features are most prominent in the intermediate portion of this region, at least one of these features was considered the minimum necessary criterion to include adjacent tissue in the entorhinal area. Second, we used morphometric measurements (neuronal size and density as well as subdivisional volume and laminar thickness) to support our qualitative evaluation. Third, we have applied to the human ERC the conventional cytoarchitectonic nomenclature of the entorhinal cortex used previously in studies of non-human primates. This allows a more accurate extrapolation of the available numerous experimental anatomical, physiological and psychological data on this region to the human. As in the monkey, the five main subareas were recognized in the human (prorhinal, lateral, intermediate, sulcal and medial) but three required further subdivision (intermediate, sulcal and medial). The morphometric results obtained suggested a progression of the human entorhinal cortex from the peripheral to the central subareas, with the intermediate subarea (281) as the most complete entorhinal subdivision. Compared with non-human primates, the human ERC not only retains the basic periallocortical organization but also demonstrates further evolution. Taken together with available experimental data on the connectivity of this brain region, these results provide an anatomical basis for evaluating the ERC in human behavior.

Adult↗

PubMed1997

A qualitative and quantitative analysis of the entorhinal cortex in schizophrenia.

The entorhinal cortex (ERC) has been implicated in schizophrenia by a number of studies. There is anatomical observation of neuronal heterotopias in the rostral ERC, which is consistent with a hypothesis of neurodevelopmental abnormalities in this disease. In view of the significant cytoarchitectonic variation of the ERC throughout its rostro-caudal extent, we performed a detailed subareal analysis of the rostral two-thirds of the entorhinal cortex (ERCr) in 14 postmortem schizophrenic brains and 14 matched controls (mean ages of 48 and 47 respectively). This systematic evaluation included both a qualitative microscopic analysis of morphogenetic anomalies that would be consistent with neurodevelopmental pathology and quantitative measurements of total neuronal number, average neuronal density, laminar volume and laminar depth from the cortical surface in cytoarchitectonically matched subareas of schizophrenic and control brains. Parcellation of the entire ERC on the basis of cytoarchitectonic criteria identified five distinct regions, similar to those described in the macaque, except that in the human brain three of the regions were further divisible into two or three subareas, yielding nine distinct cellular compartments. Five rostral areas, prorhinal (Pr), lateral (28L), intermediate rostral and caudal (281r and 281c), and sulcal (28S), comprise the ERCr. Gross and microscopic examination of these subdivisions throughout the ERCr failed to reveal laminar disorganization in any of the schizophrenic brains. The brains also did not differ significantly with respect to total neuronal number, total volume and neuronal density per laminar and subareal subdivision, or laminar thickness per entorhinal subarea. However, neuronal number and density were reduced by 12-18% in Pr and 28L, suggesting that mild quantitative abnormalities may exist in the ERCr and might possibly be revealed in a larger sample of schizophrenic brains. We have failed to confirm previous reports of laminar disorganization in the ERCr in brains of patients with schizophrenia; to the extent that this region is implicated in schizophrenia, the structural changes are likely to consist of more subtle cellular disturbances.

Adult↗

PubMed1989

[Possibilities for the histochemical study of the nuclei of normal brain cells and in pathology].

Possibilities of application of some histochemical methods to studying cell nuclei of brain are reviewed considering the following techniques: hybridization histochemistry on the light and electron microscope levels, immunohistochemistry and immunoelectron microscopy, absorbtion and fluorescence histochemistry of nucleic acids, histones, non-histone proteins of chromatin, and of cell nucleus lipids, electron histochemistry. Besides, some physicochemical and molecular-biological methods are considered. Data on human brain research in the norm and upon various brain disorders are particularly provided.

Brain↗