Binocular luminance summation in young kittens and adult strabismic cats.

Normal adult cats show a 35% increase in pupil diameter when one eye is illuminated and the other occluded, rather than when both eyes are illuminated. Young kittens show significantly less binocular luminance summation than adult cats (14%). Since these kittens also show a significantly reduced pupillary response to luminance decrements, the postnatal development of binocular luminance summation reflects an increase in pupillary motility, rather than a development of binocular function. Binocular luminance summation is much reduced in esotropic cats (6%), but not in exotropic cats (33%). This finding casts doubts on the usefulness of binocular luminance summation as a measure of binocular function.

Developmental exposure of rats to a reconstituted PCB mixture or aroclor 1254: effects on long-term potentiation and [3H]MK-801 binding in occipital cortex and hippocampus.

The central nervous system is one of the target organs for polychlorinated biphenyls (PCBs). We measured the effects of maternal exposure of Long-Evans rats to a mixture of PCB congeners reconstituted according to the pattern found in human breast milk (reconstituted mixture, RM) on long-term potentiation (LTP) in two brain regions. Exposure of the dams via food started 50 days prior to mating and was terminated at birth. In the first experiment, adult male and female offspring were exposed maternally to 40 mg/kg of the RM or the commercial mixture Aroclor 1254 (A1254). LTP and paired-pulse inhibition were measured in slices of the visual cortex. In addition, the binding of [3H]MK-801 to the N-methyl-D-aspartate (NMDA) receptor-ion channel as well as the [3H]muscimol binding to the GABA-A receptor in membrane preparations from the occipital cortex and hippocampus were determined. LTP as well as [3H]MK-801 binding were significantly reduced in the cortex following PCB exposure, while [3H]MK-801 binding in the hippocampus was not affected. In a succeeding experiment, LTP was determined in cortical and hippocampal slices from rats at postnatal days 10 to 20, following exposure to 0, 5, or 40 mg/kg of the RM. Cortical LTP was significantly affected by the RM while no effects were seen in hippocampal LTP. Taking the two experiments together, PCB exposure significantly reduced LTP, as well as [3H]MK-801 binding, in the cortex and had no effect in the hippocampus. The LTP deficits can only partly be related to the reduction of binding sites to the NMDA receptor; other PCB-induced neurochemical changes have to be assumed.

Acute lead exposure transiently inhibits hippocampal neuronal activities in vitro.

The effects of acute lead exposure on extracellularly recorded evoked responses in the CA1 region of hippocampal slices were investigated. Field potentials in response to paired-pulse stimulation were assessed while perfusing the slices with normal media and media containing lead in concentrations of 0.2 microM to 53 microM. The evoked population excitatory postsynaptic potentials decreased during lead exposure to a lesser extent than the orthodromically evoked population spike, whereas the presynaptic fiber volley remained unchanged. The maximal inhibition of the orthodromically evoked responses depended strongly on the lead concentration. The input-output relations of the orthodromic responses obtained during perfusion with lead significantly differed from those during control conditions. The somatic short-term potentiation obtained by paired-pulse stimulation increased during the lead exposure. Lead seemed to inhibit the evoked activities only transiently: within 20 min after lead onset, the recorded responses had reached the control level again in spite of further lead perfusion. In contrast to the orthodromically evoked responses, the antidromically evoked population spikes remained constant at all concentrations used. It is concluded from these results that lead acts presynaptically in the hippocampal slice preparation. Additionally, lead interferes with non-synaptic processes at the pyramidal neurons in the CA1. Possible influences of lead over different neurotransmitter systems are discussed.

Chronic prenatal and postnatal Pb2+ exposure increases [3H]MK801 binding sites in adult rat forebrain.

We have measured the binding of [3H]MK801 to the N-methyl-D-aspartate (NMDA) receptor-ion channel in membrane preparations from adult rat forebrain exposed to lead (Pb2+) during gestation, lactation, and postweaning. Our results indicate a 30.9% increase in the number of [3H]MK801 binding sites in Pb2+ exposed animals relative to controls. No significant changes in the affinity constant were observed. The level of blood Pb2+ for which such changes were measured was 13.9 +/- 2.8 micrograms/dl. These results indicate that alterations in the NMDA receptor-ion channel complex are present at blood Pb2+ levels which are environmentally relevant and suggest that chronic Pb2+ exposure during development can influence the NMDA receptor complex in the adult rat brain.

Effects of maternal lead exposure on functional plasticity in the visual cortex and hippocampus of immature rats.

We examined the amount of long-term potentiation (LTP) in slices from the visual cortex and hippocampus of pre- and postnatally lead-exposed rats and controls at postnatal days (PND) 12-20. A dietary lead intake of 750 ppm by the dams resulted in a mean blood lead concentration in the suckling offspring of about 17' micrograms/dl. While high-frequency stimulation (HFS) of the white matter induced LTP of the field potentials in layers II/III in cortical slices of ten out of the 14 control rats, only three of the twelve lead-exposed rats showed a small amount of LTP. However, in slices from seven of the twelve lead-exposed rats a long-term depression was found following HFS. Furthermore, paired-pulse inhibition was weaker in cortical slices from the lead-exposed as compared to the control rats. In the CA1 hippocampal region the amount of LTP was significantly reduced in the lead-exposed group only in slices taken from rats at PND 16-20, while no differences were seen in slices from younger animals. It is concluded that even low level lead exposure impairs functions of the visual cortex in the immature rat. We suggest that the developing hippocampus is able to compensate for lead-induced functional deficits in the 2nd postnatal week, being more vulnerable at older ages.

Postnatal development of synaptic plasticity in the CA3 hippocampal region of control and lead-exposed Wistar rats.

The object of this study was to compare the postnatal development of mossy fiber potentiation (MFP) and paired-pulse facilitation in the CA3 region of control and led-exposed rats. The postnatal development of MFP was not influenced by the chronic pre- and postnatal lead exposure nor did we find a statistically significant impairment of MFP in region CA3 following lead exposure in the four age groups studied. In contrast to the adult animals, in the three immature groups of the control as well as the lead-exposed animals MFP was preceded by a posttetanic depression after which MFP developed slowly. The results of the paired-pulse procedure depended both on the age and on the interstimulus interval (ISI) in control and lead-exposed animals. The differences between control and lead-exposed rats were statistically significant only in the adult animals at an ISI of 10 ms. In this case paired-pulse stimulation resulted in an increase of the second evoked response relative to the first response in the lead-exposed animals while the same procedure decreased the second evoked response in the control animals. It is concluded that although low lead exposure had no effect on the expression of MFP in hippocampal CA3 region, inhibitory mechanisms as revealed by paired-pulse stimulation are impaired by lead in adult rats.

Inhibition of long-term potentiation in developing rat visual cortex but not hippocampus by in utero exposure to polychlorinated biphenyls.

The neurotoxic potential of polychlorinated biphenyls (PCBs) depends on the structure of the congener as well as on the age of the exposure. We exposed rats prenatally to a coplanar congener (PCB-77) or to a non-coplanar congener (PCB-47) and measured the amount of long-term potentiation (LTP) at postnatal days 11-19 in the visual cortex and hippocampus. While PCB-77 exposure affected LTP statistically significantly in cortical but not hippocampal slices, the exposure to PCB-47 was much less effective.

Long-term potentiation in rat hippocampal slices is impaired following acute lead perfusion.

Orthodromically evoked field potentials were recorded in the CA1 region of hippocampal slices while perfusing the slices with media containing lead acetate. High-frequency stimulation (HFS) was applied to the stratum radiatum during lead perfusion. In half of the slices investigated, HFS resulted in an initial increase of the evoked responses which decayed again after about 10 min. In the other half the evoked responses increased only after the washout of lead and this potentiation was comparable to untreated controls. The lead-induced depression of the long-term potentiation might be related to the behavioral deficits observed in chronically lead-exposed mammals.

Maternal exposure to polychlorinated biphenyls inhibits long-term potentiation in the visual cortex of adult rats.

Rats were exposed prenatally to the coplanar congener 3,3',4,4'-tetrachlorobiphenyl (TCB). The amount of long-term potentiation (LTP) was measured in slices from the visual cortex and hippocampus of the adult males as well as of controls. While in the cortical slices from the controls a stable LTP could be induced, LTP was inhibited in the TCB-exposed rats. In hippocampal slices, the amount of LTP was not significantly different between the two groups. Our results suggest that the visual cortex of adult animals is functionally altered by TCB if the exposure takes place during embryonic development.

Temporal integration in amblyopic vision.

Amblyopic subjects were tested on different visual tasks which required temporal integration of successively presented stimuli: a figure had to be detected whose components were displayed successively and hidden in spatio-temporal noise. The time interval T over which the figure elements were dispersed was varied and the longest T value still compatible with figure detection was determined. In all subjects these T values were considerably longer for the normal than for the amblyopic eye. A missing square had to be detected in a checker-board of 3 X 3 squares that was presented in two successive frames, each frame containing 4 squares. With the normal eye, identification of the missing square was possible over considerably longer interstimulus intervals (ISIs) than with the amblyopic eye. Changes had to be detected in two patterns of randomly distributed squares that were presented successively with varying ISI whereby one square was added or subtracted in the second pattern. With the normal eye, detection of changes was possible over much longer ISIs than with the amblyopic eye. These experiments show a deficit of the amblyopic visual system to integrate temporally separated stimuli. We conclude that amblyopia is associated with a marked reduction of the duration of visual persistence and suggest that this is due to shortening of normally sustained neuronal responses.

Temporal integration in the visual system: influence of temporal dispersion on figure-ground discrimination.

Psychophysical measurements were carried out with a microcomputer-controlled matrix of 32 X 32 light emitting diodes to determine temporal parameters of figure-ground separation processes. The task was to detect a figure that was dispersed in time. Between each two figure elements n noise elements were interspersed. The results of these experiments indicate that the discrimination of figures hidden in dynamic noise is possible even if figure elements are dispersed in time over several hundred milliseconds. The maximal dispersion time still compatible with figure discrimination (Tmax) depends critically on the number n of interspersed noise elements, on the subject's expectancy and on the number of elements used for the generation of the figure. For simple figures such as triangles Tmax could be as long as 1.5 sec when n was 4. Our experimental results suggest that the neuronal representation of the briefly displayed (less than 6 msec) pattern elements outlasts their physical presence by at least 400 msec. This persistence of neuronal representations must occur at a level of processing where retinotopy is still preserved, since the only cue for figure-ground discrimination is the difference in the local density of figure and noise elements.

Neurophysiological aspects of hippocampal neurotoxicity.

Identification and analysis of chemical neurotoxicity in the central nervous system deals with synaptic transmission and plasticity. The hippocampus slice technique rendered a powerful tool for electrophysiological analysis of these events as modulated by neurotoxic chemicals. It does not only allow the detection of potentially harmful compounds, but also the elucidation of their mechanism of action. This might render it possible to analyze the risk of neurotoxic chemicals on the basis of quantitative data.

Effects of chronic low level lead exposure on the expression of GFAP and vimentin mRNA in the rat brain hippocampus analysed by in situ hybridization.

In this study we used in situ hybridization to examine the effects of chronic low level lead toxicity during different periods of brain development. Low level lead is known to affect astroglia. GFAP and Vimentin were chosen as glialtypic markers for neurotoxicity. The effects of lead were investigated on male Wistar rats. Animals were divided into four groups: a control group, a permanent group exposed during gestation, lactation and post-weaning (E0-P100), a perinatal group exposed during gestation and postnatally until weaning (E0-P16), and a post-weaning exposed group (P16-P100). All experimental animals were fed a diet containing 750 ppm lead acetate. With respect to Vimentin mRNA no major differences could be detected among the treatment groups. Significant differences in GFAP mRNA levels were detected in the post-weaning group relative to controls. In this group we observed a strong increase of GFAP mRNA in the polymorphic zone of the dentate gyrus and in the CA1 region of the hippocampus. Permanent and perinatal groups showed no overt changes compared to controls. Our findings suggest that an irritation of the mature astrocyte results in a change from the quiescent to the reactive state. The majority of astrocytes that have been exposed during their development and differentiation fail to react even if the exposure is continued to adulthood. This suggests an irreversible insult by low level lead exposure during this period of time.

Neurobehavioral and neurophysiological observations in six year old children with low lead levels in East and West Germany.

Within a larger comparative environmental health screening program in East and West Germany neurobehavioral and neurophysiological measures were taken in 367 six year old children in Leipzig (N = 179), Gardelegen (N = 68), and Duisburg (N = 120). Lead concentrations from venous blood samples (PbB) and from deciduous teeth (PbT) were measured as markers of environmental lead exposure by electrothermal AAS. Dependent variables included four subtests from NES1 (tapping, reaction time, pattern comparison, and Benton visual retention), as well as VEP-latencies (N2, P100, N3) evoked by checkerboard patterns of different size and contrast. The overall median blood lead-concentration was 5 micrograms/dl (range: 1.3-19.0 micrograms/dl), and the corresponding tooth lead-concentration was 2 micrograms/g (0.2-14 micrograms/g). The 95-percentile of the overall frequency distribution for PbB was below 10 micrograms/dl. Associations between markers of lead-exposure and neurobehavioral or neurophysiological outcome were assessed by means of multiple linear or logistic regression analyses. After adjusting for relevant confounders/covariates significant (p < 0.05) Pb-related deficit was found for tapping and pattern recognition with respect to PbB but not PbT. No such associations could be established for VEP-latencies. These results are compatible with the hypothesis that subtle neurobehavioral dysfunction in children may be associated with very low PbB.

Synaptic plasticity in the CA1 and CA3 hippocampal region of pre- and postnatally lead-exposed rats.

The effects of low level lead exposure on synaptic plasticity in hippocampal regions CA1 and CA3 were determined in adult rats in vitro. In the CA3 region the NMDA (N-methyl-D-aspartate)-independent mossy fiber-CA3 synapse potentiation was not influenced by chronic pre- and postnatal lead exposure, while in the same rats, in the CA1 region the NMDA-dependent long-term potentiation was slightly reduced as compared to controls. Paired-pulse facilitation was neither impaired in CA1 nor in CA3 region in the lead-exposed rats. These findings suggest that NMDA-dependent forms of synaptic plasticity are more susceptible to chronic low level lead exposure than NMDA-independent forms of potentiation or paired-pulse facilitation.

Impairment of long-term potentiation and learning following chronic lead exposure.

Chronic lead exposure during brain development is known to affect functions of the central nervous system. We exposed rats chronically to low levels of lead at different developmental stages in order to determine the most sensitive periods of exposure. Active avoidance learning and hippocampal long-term potentiation were tested in the same animals. If the exposure period comprised the prenatal and the early postnatal phase and was continued into adulthood, learning as well as long-term potentiation were impaired. Starting the exposure not before 16 days postnatally, however, neither affected learning nor hippocampal potentiation. These results reflect the higher vulnerability of the immature as compared to the mature hippocampus to lead-induced functional deficits.

Cognitive and sensorimotor functions in 6-year-old children in relation to lead and mercury levels: adjustment for intelligence and contrast sensitivity in computerized testing.

Within a larger environmental health screening program neurobehavioral measures were taken in 384 6-year-old children (mean age 74 months) in the cities of Leipzig, Gardelegen, and Duisburg. Lead concentrations in venous blood samples (PbB) and urinary mercury excretion in 24-h samples (HgU) were measured as markers of environmental exposure by electrothermal AAS. Dependent variables included two subtests from the WISC [vocabulary (V) and block design (BD)] as well as five tests from the NES2 [pattern comparison, pattern memory, tapping, simple reaction time, and the continuous performance test (CPT; child version)]. In addition, visual functions [visual acuity (TITMUS-test) and contrast sensitivity (FACT)] were tested as covariates. The overall average PbB (geometric mean) was 42.5 microg/l (upper 95% value = 89 microg/l). The overall average mercury excretion (HgU) was 0.16 microg/24 h. Whereas no significant or borderline associations between HgU and any of the target variables was found, significant negative associations were observed between PbB and verbal intelligence (WISC vocabulary but not WISC Block Design) and false-positive responses (false alarms), as well as false-negative responses (miss) in the CPT. Whereas parental education was the most important confounder for WISC performance, visual contrast sensitivity and computer familiarity also proved predictive for performance in several computer-based NES subtests. It is concluded that non-IQ measures, namely measures of sustained attention, are negatively affected in children with 95% of blood-lead levels below 90 microg/l, even after adjustment for intelligence and contrast sensitivity, whereas the causative role of lead in altering IQ functions remains somewhat equivocal, because important covariates could not be controlled for.

Visual functions in 6-year-old children in relation to lead and mercury levels.

Within a larger comparative environmental health screening program in East and West Germany we investigated functions of the developing visual system in field experiments in a total of 384 children living in three different areas. Visual functions were assessed neurophysiologically by visual-evoked potentials (VEPs) and psychophysically by measuring the contrast sensitivity (CS). Blood lead concentrations and urinary mercury levels were used as markers of environmental and/or amalgam-derived exposure, respectively. The relationships among lead and mercury concentrations and the neurophysiological and psychophysical outcomes were investigated by means of linear regression analysis. After adjusting for confounding effects, statistically significant lead-related changes were found only for some of the VEP interpeak latencies, while some of the CS values were significantly reduced with increasing mercury concentrations. All other outcome variables were not significantly related to lead or mercury levels. It is concluded that even at blood lead levels in the range of 14 to 174 micrograms/l and at very low urinary mercury levels subtle changes in visual system functions can be measured.

Speech errors in Alzheimer's disease: reevaluating morphosyntactic preservation.

Researchers studying the speech of individuals with probable Alzheimer's disease (PAD) report that morphosyntax is preserved relative to lexical aspects of speech. The current study questions whether dividing all errors into only two categories, morphosyntactic and lexical, is warranted, given the theoretical controversies concerning the production and representation of pronouns and closed-class words in particular. Two experiments compare the speech output of 10 individuals with Alzheimer's disease to that of 15 healthy age- and education-matched speakers. Results of the first experiment indicate that the pattern of errors in the speech of participants with mild PAD reflects an across-the-board increase in the same types of errors made by healthy older speakers, including closed-class and morphosyntactic errors. In the second task, participants produced a grammatical sentence from written stimuli consisting of a transitive verb and two nouns. Only adults with Alzheimer's disease had difficulties with this task, producing many more closed-class word errors than did healthy older adults. Three of the participants with PAD produced nearly agrammatic speech in this task. These 3 people did not differ from the rest of the PAD group in age, education, working memory, or degree of semantic impairment. Further, error rates on the two tasks were highly correlated. We conclude that morphosyntax is not preserved in the speech output of individuals with PAD, but is vulnerable to errors along with all aspects of language that must be generated by the speaker. We suggest that these results best support a model of speech production in which all words are represented by semantic and grammatical features, both of which are vulnerable to failures of activation when there is damage or noise in the system as a result of pathology, trauma, or even divided attention.