Christine F. Hohmann

Neonatal lesions of the basal forebrain cholinergic neurons result in abnormal cortical development

The effect of electrolytic lesions of the neonatal forebrain on the morphogenesis of the mouse neocortex has been examined. Balb/C mice were lesioned unilaterally within 24 h of birth. The development of cortical cytoarchitecture was assessed in Nissl-stained sections, and the levels of presynaptic markers for cholinergic, noradrenergic and serotonergic afferents were measured in the fronto-parietal cortex ipsilateral and contralateral to the lesion at various postnatal ages and in adulthood. The basal forebrain (nBM) lesion resulted in a transient but severe reduction of cortical cholinergic markers and in abnormal cortical cytoarchitecture. Cytoarchitectural abnormalities were expressed as delay in the emergence of differentiated cell populations and affected sequentially more superficial layers with maturation following lesion. Furthermore, the location and extent of these morphologic abnormalities appeared to correlate with the degree of cholinergic denervation. Cortical monoamines were also temporarily reduced as a result of the lesion; however, pharmacologic lesions of the monoaminergic projections alone did not result in the abnormal cortical cytoarchitecture. Thus, the basal forebrain cholinergic projection appears to serve a role in regulating cortical differentiation.

Basal Forebrain Cholinergic Neurons and Alzheimer’s Disease

Although neuropathological and epidemiological studies have long indicated Alzheimer’s dementia (AD) as a major cause of cognitive deterioration in the elderly (Larsson et al., 1963; Kay et al, 1964; Roth et al, 1967), the reports of Davies and Maloney (1976) and Bowen et al (1976) describing selective deficits in cholinergic synaptic neurochemical markers in the cortex and hippocampus of Alzheimer’s patients provoked a paradigm shift in the thinking of the neuroscientific community concerning the pathobiology of this disorder. Thus, in the 7-year period prior to these two publications, approximately 30 articles per annum appeared in the medical/scientific literature on AD, whereas in the 5-year period after these reports, the annual number of publications increased nearly 10-fold. While other factors such as the increasing interest in geriatric medicine and the growing appreciation of the social and economic implications of AD with regard to the increasing lifespan of individuals in Western society undoubtedly contributed to the burgeoning medical and scientific interest in the disorder, the discovery of selective neurotransmitter deficits in AD clearly had a tremendous impact.

A long-acting cholinesterase inhibitor reverses spatial memory deficits in mice

The effects of the long-acting acetylcholinesterase (AChE) inhibitor, galanthamine, on spatial memory were investigated in mice. Mice received ibotenic acid or sham lesions to the nucleus basalis magnocellularis (nBM). Groups of nBM-lesioned and control mice were then trained on a modified Morris swim maze task. Each mouse was first placed on a platform and then into quadrants of the swim tank in a random order. Time required to find the hidden platform was measured. In different phases of testing, the animal had to find a platform that either remained in the same quadrant (reference memory component) or was moved daily (working memory component). The nBM-lesioned mice took significantly longer to find the platform as compared to controls on the working, but not on the reference, memory component of the task. Galanthamine (5.0 mg/kg, IP), given 3.5 hours before testing, improved performance on the working memory task in nBM-lesioned mice by 70% and strikingly impaired performance in controls. Galanthamines ability to reverse cognitive deficits induced by nBM lesions and its comparatively long half-life suggest that it may be effective in treating the central cholinergic deficits in Alzheimers disease patients.

Developmental expression of somatostatin in mouse brain. I. Immunocytochemical studies.

The postnatal development of the distribution of somatostatin immunoreactive (SOMLI) neurons and fibers in the forebrain of the Balb/C mouse and their relationship to cholinergic afferents have been examined. SOMLI was first discernable in the hypothalamus on postnatal day (PND) 3 and increased gradually to reach adult levels by PND 30. In the limbic system, SOMLI is detectable at birth. In all other structures of the forebrain, SOMLI could be observed by PND 3 but the distribution, density and morphology of the immunoreactive neurons evolved over the following 2-3 weeks. In general, SOMLI cells and fibers increased for 1-3 weeks after their initial appearance and subsequently declined to achieve adult levels. The distribution pattern of SOMLI elements in adult mouse brain was similar to previous reports in rat with a few notable differences in thalamus, olfactory structures and, to a lesser degree, cortex and hippocampus. The temporal pattern of SOMLI expression in extrahypothalamus forebrain regions, during development, suggests a role of this peptide in differentiation and synapse formation. Such an hypothesis receives further support from neonatal lesions of the basal forebrain which resulted in transient cortical cholinergic deafferentation, a delay of cortical differentiation and a transient increase in the number of SOMLI cells in cortex.

Developmental regulation of adult cortical morphology and behavior: An animal model for mental retardation ☆

The purpose of this study was to examine the behavioral performance in adult mice which, as neonates, had received lesions to cortically projecting, cholinergic basal forebrain neurons. The nucleus basalis magnocellularis (nBM) provides the primary cholinergic innervation to cerebral cortex. Lesions in the nBM in neonatal mice result in transient cholinergic denervation and persistent abnormalities in cortical morphology and cytoarchitecture. These cortical abnormalities resemble pathologies observed in a number of developmental disabilities in humans, including Down Syndrome. Balb/CByJ mice received lesions to the nBM 12–24 hr after birth; littermates served as controls. Behavioral testing began 8 weeks after the lesion and included assessments of spontaneous motor activity, retention (a passive avoidance task) and cognition (the Morris swim task). Following behavioral testing, a subset of mice was killed for Nissl and acetylcholinesterase (AChE) histology. The cortical morphology in these brains was evaluated and ranked by the experimenter, who was blind to the lesion and behavioral studies. The lesioned mice exhibited increased spontaneous activity as compared to littermate controls. The lesioned mice were also severely impaired in performance of the retention and cognitive task; they showed decreased passive avoidance retention latencies and increased swim maze latencies as compared to controls. The brains of all of the lesioned mice exhibited cortical morphological abnormalities that ranged from slight to severe. Cortical AChE intensity and distribution in the brains of the lesioned mice, however, were comparable to those of controls. In correlation studies of behavioral and morphological data, motor activity did not correlate with either passive avoidance retention or swim maze latencies. Additionally, cortical cytoarchitectural abnormalities did not correlate with motor activity. Cortical cytoarchitectural abnormalities did, however, correlate with both passive avoidance and swim maze latencies, i.e. severely abnormal cortical morphology predicted low passive avoidance retention latencies and high swim maze latencies. These data indicate that cortical cytoarchitectural abnormalities resulting from nBM lesions in neonates correlate with impairments on the cognitive task, but not with the activity measures, in adult mice. Thus, in this lesion model, and by extrapolation in developmental disabilities in humans, structural changes in the cortex which result from transient disruption of cortical cholinergic innervation may lead to persistent cognitive impairments in adulthood.

Age-related recurrence of basal forebrain lesion-induced cholinergic deficits

Lesions of basal forebrain cholinergic nuclei projecting in neocortex have recently been employed as an animal model for the cholinergic deficits in Alzheimers disease. However, unlike Alzheimers patients, whose deterioration appears to be progressive and irreversible, basalis lesioned rats usually recover both behaviorally and neurochemically within several months after the lesion. We now demonstrate that this recovery may be a function of the age of the rat and that cholinergic deficits re-occur in the aged rat. Choline acetyltransferase (ChAT) activity and [3H]hemicholinium-3 ([3H]HCh-3) binding are reduced in cortex ipsilateral to ibotenic acid lesions in the 12-month postlesion rat following an initial recovery to normal levels by about 3 months postlesion. The recurrence of decrease of cholinergic markers is not a consequence of a non-specific age-related decline since the activity of glutamic acid decarboxylase remains constant between 3 and 12 months postlesion.

Transient postnatal elevation of serotonin levels in mouse neocortex.

Serotonin (5-HT), norepinephrine (NE) and 5-hydroxyindoleacetic acid (HIAA) levels were measured during ontogeny of frontoparietal cortex in Balb/C mice by high-pressure liquid chromatography (HPLC) with electrochemical detection. Unlike NE, the concentration of 5-HT was transiently elevated to more than twice the adult level during the first postnatal week; this was accompanied by increased HIAA content comparable to the adult, indicating elevated levels of 5-HT release. Since a transient hyperplasia of 5-HT-immunoreactive fibers and uptake sites has been observed previously in the same cortical areas, the transient elevation of 5-HT levels may play an important role in shaping early postnatal morphogenetic events in neocortex.

Long-term effects of basal forebrain lesions on cholinergic, noradrenergic and serotonergic markers in mouse neocortex

Lesions of basal forebrain cholinergic neurons projecting to cerebral cortex and hippocampus have recently been exploited as animal models for some of the neurochemical and behavioral deficits of Alzheimers disease. We have observed that electrolytic lesions of cholinergic basal forebrain nuclei can lead to morphological plasticity in adult mouse cortex. In the present study, the acute and chronic sequelae of basal forebrain electrolytic lesion on cortical synaptic chemistry have been examined. In addition to choline acetyltransferase (ChAT) activity, levels of norepinephrine and of serotonin were reduced within a week after the lesion. Recovery of ChAT activity and of serotonin levels began within a month after the lesion. Serotonin type 2 receptor binding exhibited an acute reduction after the lesion in ipsilateral cortex, followed later by a chronic bilateral decrease. No significant changes in beta-adrenergic receptors were apparent at any time after the lesion despite a permanent and bilateral reduction of norepinephrine levels after the lesion. The potential significance of these results for cortical plasticity regulation and Alzheimers disease is discussed.

Transplantation of brain tissue from murine trisomy 16 into euploid hosts: Effects of gene imbalance on brain development

Publisher Summary This chapter describes preliminary results from studies involving the transplantation of cortex from trisomy 16 (Ts16) and euploid littermates at days 15/16 of gestation (E15/16) into neonatal euploid hosts. Aside from the histological analysis of Nissl stained sections, acetylcholinesterase (AChE) expressing fibers is visualized as a presynaptic marker for developing cholinergic innervations from the basal forebrain. In addition, immunocytochemical and/ or in situ hybridization methods have been used to visualize the expression and gene product of growth associated protein 43 (GAP43) and preprosomatostatin (ppSmst). GAP43, also known as F1, PP46, and B50, is expressed in association with axon growth during development, regeneration, and plasticity; and therefore, it may play an important role in postmitotic neuronal differentiation. Somatostatin (Smst), on the other hand, shows a transient peak of expression during the second and third weeks after birth, the period of cortical cell differentiation and synapse formation. Furthermore, Smst expression appears to be regulated, in part, by cholinergic innervations. Many of the cells expressing Smst during cortical development are probably members of a class of early subplate neurons of the Cajal–Retzius type. These neurons presumably play a transient role in cortical morphogenesis and appear to die as development proceeds. Quantifications of the mitochondrial RNA (mRNA) for both GAP43 and ppSmst indicate that they are over-expressed in Ts16 fetal brains, in levels consistent with a simple gene dosage effects. The chapter discusses the role of the host brain in correcting the overexpression of these 2 genes in the cortical grafts.

Neuroscience and Biobehavioral Reviews: Introduction

Grain loss monitors are instruments which are installed on combine harvesters that make possibility to measure grain loss on different parts of combine. The instrument permits combine operator to use proper ground speed to keep grain loss in an acceptable range. There was used an indicator system to measure which flows on straw walker and sieves that indicates loss rate continuously. According to the executive office of wheat in the Ministry of Agriculture, average combine processing losses was reported from 1.72 to 2.41% during years 2005 till 2007 that its far from ASAE standard was expected, so in order to control this losses the research was necessary in this case as explained. In this study, grain loss monitors was mounted behind the straw walker and sieves of John Deer 955 combine harvester. Crop and machine performance parameters then were measured as grain moisture content, yield, combine ground speed and processing loss, respectively. Combine harvester equipped with grain loss monitor was assessed on the wheat harvest. During harvesting plots, loss rate was measured and indicated using diodes of grain loss monitor to the operator. The loss rate shows combine processing loss. There is sound on monitors that notify to operator that which part has a more loss than standard range. It will be then adjusted and continued to harvesting. In order to evaluate instrument precision, indicated loss with measured loss was compared and investigated. Treatments of this study were: 1ground speed of combine harvester as a main plot, 2combine drum (cylinder) speed as a sub plot. Experimental design was split plot in a completely randomized block design with three replications. The results of two years research and study show that the processing loss of combine harvester was about 1% and adapted with ASABE standard No. S343.3 on 10-12% grain moisture content and 750 rpm drum speed. Also, there was no difference between measured and expected processing loss based on zero hypothesis; means loss rate indicated using grain loss monitor adapted with measured processing loss.