Forebrain Function Research Articles

Revista española de medicina nuclear

Physical exercise is now generally considered as a strategy to maintain cognitive abilities and to prevent age-related cognitive decline. In the present study, Wistar rats were subjected to moderate intensity treadmill exercise for 6 months prior to sacrifice at 12-, 24- and 32-month of age. This chronic physical intervention was tested on motility in the Open field (OF). Cognitive functions were measured in the Morris water maze (MWM) for spatial learning and in the Novel object recognition (NOR) tests. Since learning and memory are closely associated with cholinergic forebrain function ChAT fiber density after exercise training was assessed in hippocampus, and motor- and somatosensory cortical areas. Furthermore, quantification of ChAT-positive fiber aberrations as a neuropathological marker was also carried out in these brain areas. Our results show that in OF chronic exercise maintained horizontal locomotor activity in all age groups. Rearing activity, MWM and notably NOR performance were improved only in the 32-months old animals. Regarding cholinergic neuronal innervation, apart from a general age-related decline, exercise increased ChAT fiber density in the hippocampus CA1 area and in the motor cortex notably in the 32-months group. Massive ChAT fiber aberrations in all investigated areas which developed in senescence were clearly attenuated by exercise. The results suggest that moderate intensity chronic exercise in the rat is especially beneficial in advanced age. In conclusion, chronic exercise attenuates the age-related decline in cognitive and motor behaviors as well as age-related cholinergic fiber reduction, reduces malformations of cholinergic forebrain innervation.

Changes in forebrain function from waking to REM sleep in depression: preliminary analyses [of 18F]FDG PET studies

Based on recent functional brain imaging studies of healthy human REM sleep, we hypothesized that alterations in REM sleep in mood disorder patients reflect a functional dysregulation within limbic and paralimbic forebrain structures during that sleep state. Six unipolar depressed subjects and eight healthy subjects underwent separate [ 18F]2-fluoro-2-deoxy- d-glucose ([ 18F]FDG) PET scans during waking and during their first REM period of sleep. Statistical parametric mapping contrasts were performed to detect changes in relative regional cerebral glucose metabolism (rCMRglu) from waking to REM sleep in each group as well as interactions in patterns of change between groups. Clinical and EEG sleep comparisons from an undisturbed night of sleep were also performed. In contrast to healthy control subjects, depressed patients did not show increases in rCMRglu in anterior paralimbic structures in REM sleep compared to waking. Depressed subjects showed greater increases from waking to REM sleep in rCMRglu in the tectal area and a series of left hemispheric areas including sensorimotor cortex, inferior temporal cortex, uncal gyrus-amygdala, and subicular complex than did the control subjects. These observations indicate that changes in limbic and paralimbic function from waking to REM sleep differ significantly from normal in depressed patients.

Altered cholinergic function in the basal forebrain of girls with Rett syndrome.

Rett syndrome (RS) is a neurodevelopmental disorder that is predominant in females and is associated with cortical atrophy, stereotyped hand movements and severe mental deficiency. Previous studies have demonstrated a significant decline in number of choline acetyltransferase (ChAT)-containing neurons throughout the forebrain of RS girls. The loss of these ChAT-positive cells may be caused by a lack of nerve growth factor (NGF). In the current study, cortical levels of NGF were normal in RS girls as compared to age-and sex-matched controls. The number of neurons within the basal forebrain that express the 75 kDa (p75) low-affinity receptor for NGF was unchanged. In contrast, the number of ChAT-positive neurons was significantly decreased. The results suggest that normal amounts of NGF are available for binding to the p75 receptor and for retrograde transport to forebrain cholinergic cells, however, these neurons do not respond by producing the ChAT protein that is necessary for the production of the neurotransmitter acetylcholine.

Cognitive functions of the basal forebrain

Studies of the function of the basal forebrain have focused on cholinergic neurons that project to cortical and limbic structures critical for various cognitive abilities. Recent experiments suggest that these neurons serve a modulatory function in cognition, by optimizing cortical information processing and influencing attention.

CDNA Cloning, Chromosomal Localization, and Expression Pattern ofEPLG8,a New Member of theEPLGGene Family Encoding Ligands of EPH-Related Protein-Tyrosine Kinase Receptors

By screening a human fetal brain cDNA library under low stringency using cDNA encoding the mouse ligand of Cek5 as a probe, we have isolated a novel cDNA belonging to theEPLGgene family. This family encodes ligands of EPH-related tyrosine kinase receptors. Since the novel gene is the eighth member of theEPLGgene family, it is designatedEPLG8.The deduced amino acid sequence ofEPLG8suggests that it encodes a transmembrane protein that is most related to those encoded byEPLG2andEPLG5.We mapped theEPLG8gene to human chromosome 17p11.2–p13.1 by PCR screening of human–rodent somatic cell hybrid panels. In the midterm fetus,EPLG8mRNA is expressed at the highest level in brain, followed by heart, kidney, and lung. In the adult,EPLG8mRNA expression is restricted to brain. These data suggest that LERK-8, the protein encoded byEPLG8,is important in brain development as well as in its maintenance. Moreover, since levels ofEPLG8expression were particularly high in several forebrain subregions compared to other brain subregions, LERK-8 may play a pivotal role in forebrain function.

Nerve Growth Factor, Central Nervous System Apoptosis, and Adrenocortical Activity in Aged Fischer-344/Brown Norway F1 Hybrid Rats

During aging there is a progressive loss of neuronal function in the basal forebrain that results in cognitive impairment and cholinergic deficits. While altered neurotrophin (NT)-mediated signal transduction may account for some age-associated deficits, there are differences in the extent of NT responsiveness among different laboratory rat strains. Here we measured nerve growth factor (NGF) protein levels and fragmented DNA in the CNS, and basal and NGF-stimulated activity levels of the hypothalamus-pituitary-adrenocortical axis (HPAA) in 3-, 18-, and 30-month-old Fischer-344/Brown Norway rats. Our results show that while there is no age-associated differences in NGF protein levels, in aged Fischer-344/Brown Norway rats, there are increases in levels of immunoreactive fragmented DNA in the CNS and in adrenocortical responses to the peripheral administration of NGF. These data contribute to the characterization of the Fischer-344/Brown Norway F1 hybrid rat and provide baseline values useful for future studies on aged CNS.

Topographical distribution of NADPH-diaphorase activity in the central nervous system of the frog, Rana perezi.

The distribution of NADPH-diaphorase (ND) activity was histochemically investigated in the brain of the frog Rana perezi. This technique provides a highly selective labeling of neurons and tracts. In the telencephalon, labeled cells are present in the olfactory bulb, pallial regions, septal area, nucleus of the diagonal band, striatum, and amygdala. Positive neurons surround the preoptic and infundibular recesses of the third ventricle. The magnocellular and suprachiasmatic hypothalamic nuclei contain stained cells. Numerous neurons are present in the anterior, lateral anterior, central, and lateral posteroventral thalamic nuclei. Positive terminal fields are organized in the same thalamic areas but most conspicuously in the visual recipient plexus of Bellonci, corpus geniculatum of the thalamus, and the superficial ventral thalamic nucleus. Labeled fibers and cell groups are observed in the pretectal area, the mesencephalic optic tectum, and the torus semicircularis. The nuclei of the mesencephalic tegmentum contain abundant labeled cells and a conspicuous cell population is localized medial and caudal to the isthmic nucleus. Numerous cells in the rhombencephalon are distributed in the octaval area, raphe nucleus, reticular nuclei, sensory trigeminal nuclei, nucleus of the solitary tract, and, at the obex levels, the dorsal column nucleus. Positive fibers are abundant in the superior olivary nucleus, the descending trigeminal, and the solitary tracts. In the spinal cord, a large population of intensely labeled neurons is present in all fields of the gray matter throughout its rostrocaudal extent. Several sensory pathways were heavily stained including part of the olfactory, visual, auditory, and somatosensory pathways. The distribution of ND-positive cells did not correspond to any single known neurotransmitter or neuroactive molecule system. In particular, abundant codistribution of ND and catecholamines is found in the anuran brain. Double labeling techniques have revealed restricted colocalization in the same neurons and only in the posterior tubercle and locus coeruleus. If ND is in amphibians a selective marker for neurons containing nitric oxide synthase, as generally proposed, with this method the neurons that may synthesize nitric oxide would be identified. This study provides evidence that nitric oxide may be involved in novel tasks, primarily related to forebrain functions, that are already present in amphibians.

NOS induction by NGF in basal forebrain cholinergic neurones: evidence for regulation of brain NOS by a neurotrophin

Nerve growth factor (NGF) acts through trkA receptors to serve as a trophic factor for cholinergic neurones in the medial septal nucleus (MSN) and vertical limb of the diagonal band (VDB). Herein, we show that brain nitric oxide synthase (NOS), which synthesizes the neuromodulator nitric oxide, is selectively expressed in a large fraction of trkA-containing neurones in the MSN and VDB. Axotomy of these neurones gave evidence that NOS expressing cholinergic neurones innervate the hippocampus. NGF infusion induced a robust, specific increase in NOS expression in basal forebrain cholinergic neurones. These results indicate that brain NOS can be regulated by a neurotrophic factor and suggest that NGF influences forebrain function by regulating production of nitric oxide as well as acetylcholine.

D 1 dopamine receptor agonist-induced fos-like immunoreactivity occurs in basal forebrain and mesopontine tegmentum cholinergic neurons and striatal neurons immunoreactive for neuropeptide Y

The present study sought to determine whether the D 1 dopamine receptor agonist CY 208ndash;243 increases Fos-like immunoreactivity in neurochemically distinct populations of interneurons in the 6-hydroxydopamine-denervated striatum. In vivo microdialysis studies indicate that cholinergic interneurons in the striatum are excited by the administration of CY 208–243 and that this effect is potentiated by dopaminergic deafferentation. Since Fos is considered to be a marker of neuronal activity, we examined the overlap between CY-208–243-induced Fos-like immunoreactivity and striatal cholinergic interneurons labelled with the cholinergic marker enzyme choline acetyltransferase. Unexpectedly, cholinergic interneurons in the striatum were not found to express Fos-like immunoreactivity. However, D 1 agonist-induced Fos-like immunoreactivity was found in neurons immunoreactive for neuropeptide Y. Consequently, the failure of cholinergic neurons in the striatum to express D 1 agonist-induced Fos-like immunoreactivity does not appear to be a general property of striatal interneurons. Indeed, CY 208–243 increased Fos-like immunoreactivity in choline-acetyltransferase-positive neurons in the basal forebrain and lateral dorsal tegmental nucleus. In the case of cholinergic basal forebrain neurons, administration of CY 208–243 has been shown to enhance the release of acetylcholine from their terminals located in the frontal cortex. Thus, unlike cholinergic interneurons in the striatum, the expression of Fos-like immunoreactivity in cholinergic basal forebrain neurons is correlated with an increase in transmitter release. Choline acetyltransferase immunoreactivity was markedly reduced in cholinergic basal forebrain neurons ipsilateral to the 6-hydroxydopamine lesion. This decrease in choline acetyltransferase immunoreactivity was confined to a pocket of cortically projecting neurons located in the posterior part of the horizontal limb of the diagonal band which included the medial preoptic nucleus. Interestingly, D 1 agonist-induced Fos-like immunoreactivity was located predominantly in those cholinergic neurons which displayed depressed choline acetyltransferase immunoreactivity. Since Fos is often induced as a consequence of increased activity, it is tempting to speculate that those neurons which stained weakly for choline acetyltransferase had been excited by the D 1 agonist administration. Accordingly, the destruction of mesencephalic dopaminergic neurons with 6-hydroxydopamine may have deprived these cholinergic neurons of an excitatory D 1 receptor-mediated drive, resulting in a reduction of choline acetyltransferase immunoreactivity. These results suggest that the degeneration of nigrostriatal dopamine neurons may contribute to the loss of cholinergic basal forebrain function in Parkinson's disease.

Cortical sensory evoked potentials and communicative forebrain functions

Cortical evoked potentials were measured to visual, auditory and somatosensory stimuli in 20 subjects with serious neurodevelopmental impairments due to various etiologies. The results were compared with behavioral observations to find out whether the absence/presence of the responses corresponded to the level of social functioning. No cortical evoked potentials were elicited in two subjects, responses to the stimulation of one modality were missing in three subjects (retinal b-waves and brainstem auditory and somatosensory evoked potentials were, however, preserved in them). No communicative behavior was observed in subjects with absent responses. Ten subjects had marked deviations in the evoked potentials, the behavioral observations in them, ranging from no communication to sentenced speech. Five subjects had normal response patterns and they showed a great variety of communicative skills, including speech. The results support the view that bilateral loss of cortical somatosensory, visual, and auditory evoked potentials is a sign of loss of neural substrates of communication.

Differential regulation in the avian song control circuit of an mRNA predicting a highly conserved protein related to protein kinase C and the bcr oncogene

An RNA identified by differential cDNA cloning (HAT-2) is highly enriched in canary forebrain in areas associated with the control of complex learned behaviors and higher perceptual processes. The nucleotide sequence predicts a protein that is 96% identical to the product of the n-chimaerin gene isolated from human brain and contains two identifiable domains suggesting a novel role in signal transduction processes. One domain is similar to the sequence in protein kinase C which mediates diacylglycerol binding and regulation. The second domain is similar to a portion of BCR, a GTPase-activating protein encoded by the breakpoint cluster region gene. In male canaries examined during the song season, HAT-2 RNA shows variable expression within the song control circuit, and is notably less abundant in the three nuclei which concentrate androgens (HVC, RA and L-MAN). A fundamental function in the vertebrate forebrain and a possible role in the regulation of neural plasticity are suggested by the conserved structure and pattern of expression of this gene in the brain.

Reliability of Electroencephalogram in the Diagnosis of Brain Death

The definition of brain death includes the irreversible loss of all brainstem and forebrain functions. The electroencephalogram (EEG), used to test forebrain functions, is part of the diagnostic armamentarium and is considered necessary even after primary infratentorial lesions. A review of both the current literature as well as new data on an interrater agreement and intrarater stability study provide the basis for a discussion on the reliability of EEG recording in this context and on the definition of brain death. Under normal conditions, the presence of an electrocerebrally inactive EEG is a valid indicator of brain death. However, the reliability and accordingly the validity of the EEG is restricted by technical problems and limited intrarater stability and interrater agreement.

Distribution of galanin-like immunoreactivity in the human brain

The distribution of galanin-like immunoreactivity has been studied in complete coronal sections taken from 9 normal human brains (4 male, 5 female mean age 54, range 42–72 years). Galanin-immunoreactive cells were restricted largely to the basal nucleus of Meynert and to the supraoptic, ventromedial and posterior areas of the hypothalamus. Fibre staining was more widespread, seen throughout the hypothalamus and in the diagonal band, septum, amygdala, hippocampus and scattered throughout the cortex. This distribution may indicate a role for galanin in the modulation of hypothalamic and basal forebrain function in man.

Brain death and the persistent vegetative state: similarities and contrasts.

Brain death and the persistent vegetative state (PVS) share the following features: 1.) There is death of neurons in the brain; 2.) Both require an etiology which is capable of causing neuronal death. 3.) The potential for cognition is totally and permanently lost; 4.) Intensive medical support is usually withdrawn. In contrast, the diagnosis of brain death depends on death of the brainstem, while PVS implies permanent and total loss of forebrain function. While brainstem death can be diagnosed clinically, accurate prognosis in PVS requires additional investigation. Thus far, the EEG is the most specific test of neuronal function in the cerebral cortex. Brain death is equivalent to death, while PVS is not; management of the latter is more complex because of medical, social, ethical and legal factors.

Lesion of dopaminergic terminals in the amygdala produces enhanced locomotor response to d-amphetamine and opposite changes in dopaminergic activity in prefrontal cortex and nucleus accumbens

In a previous study using differential pulse voltammetry we demonstrated an interaction between dopaminergic activity in the amygdala and the nucleus accumbens. In the present study, by post-mortem biochemical measurements, we showed that bilateral 6-OHDA lesions of DA innervation of the amygdala leads to an increase in DA activity in the nucleus accumbens (DOPAC/DA ratio +24%) and a reduction (DOPAC/DA ratio-40%) in the prefrontal cortex. In addition, after these lesions in the amygdala, there was an increased behavioral sensitivity to d-amphetamine, demonstrated by enhanced locomotor activity. Increased understanding of the interregulations between dopaminergic activity in forebrain structures may help explain forebrain functions and/or dysfunction.

Effects of prolonged ethanol consumption on cholinergic function in the basal forebrain and memory

Korsakoff's psychosis, like other amnestic and dementing disorders in humans, is accompanied by a degeneration of the cholinergic neurons in the basal forebrain (Arendt et a[., 1983). These neutrons represent the main cholinergic input to the cerebral cortex and hippocampus (Wenk et al.., 1980), and a reduced activity of choline acetyltransferase has been reported in the hippocampus of chronic alcholics (Antuono et al., 1980). However, the pathogenetic link between prolonged consumption of alcohol, degeneration in the cholinergic system and memory dysfunction has not been established so far. Therefore, the aim of the present study was to investigate the influence of chronic ethanol intake on memory, on cholinergic function in the basal forebrain, and on the target regions of basal forebrain cholinergic cells such as the cerebral cortex and hippocampus. Male Sprague-Dawley rats (150-l8Og) were caged in groups of four and given either 20% (v/v) ethanol or tapwater as the only source of fluid. Mean daily consumption was 9.5 g/kg resulting in blood alcohol levels between 40 mg/ 100 ml (daytime) and 120 mg/100 ml (darkness). At certain time points (after 4.8, 18 and 28 weeks of ethanol consumption, and after a 4 week ethanol-week period following 4, 8, 18 and 28 weeks of ethanol intake) animals were killed by decapitation, or for acetylcholine (ACh) determinations by microwave radiation. The brain was rapidly removed and dissected. Enzyme activities were measured using slightly modified standard methods: choline acetyltransferase (ChAT, EC 2.3.1.6.) (Fonnum 1969), acetylcholinesterase (AChE, EC3.1.1.7) (Ellman et al., 1961), pyruvate decarboxylase (PDC, EC 4. I . 1 .1 .) (Dreyfus & Hauser 1965). Synaptosomes were prepared on Percoll gradients (Dunkley et al., 1986) and choline uptake was measured according to Marchbanks (1968). ACh was extracted by formic acid/ acetone (Toru & Aprison, 1066) and determined on a LKB Wallac 125 1 Luminometer (Israel & Lesbats, 1982). Alcohol blood levels were measured with a Lion Alcometer AE-Dl. Protein was determined according to Peterson (1977). Spatial and non-spatial reference and working memory were measured in an eight-arm radial maze (Jarrard, 1983) after a 4 week ethanol-free period following 8, 18 or 28 weeks of ethanol consumption. In the basal forebrain (Fig. 1) ACh levels and PDC activity showed a rather rapid decline, whereas ChAT and AChE activities decreased only slowly with the duration of ethanol intake. Choline uptake declined after an initial increase which might reflect a compensatory mechanism for the reduction in ACh and PDC activity. However, a 4 week ethanol-free period following 4 or 8 weeks of ethanol consumption reversed all changes back to control values. Changes were not fully reversible after 18 weeks of ethanol intake. After a 28 week period of ethanol consumption the decrease in all parameters persisted for the full 4 weeks of measurement. The aquisition of the spatial and non-spatial memory task was unimpaired after 8 weeks of ethanol consumption. However, after 18 weeks, reference and working memory were marginally impaired in the spatial task. After

Forebrain function: A theory about the general organization

It is suggested that the cerebral cortex is made up of many non-overlapping units which are regulated by the thalamus in such a way that just a few of them are “on” at a time. How these units are built up and by which neurones is discussed in some detail. Explanations are proposed for some psychiatric and neurological disorders. Furthermore, two memory mechanisms are discussed briefly.

Light experience during development affects asymmetry of forebrain function in chickens

The chicken brain has asymmetry of forebrain function for attack and copulation behaviors. This study reports that this asymmetry, revealed by intracranial injections of glutamate, is affected by light exposure. Eggs were incubated in 3 forced-draught incubators matched for noise, humidity and temperature control, so that light and laboratory noise were the only systematic variables. All eggs were incubated in darkness for the first 17 days of incubation after which they were allocated to one of 3 incubating conditions, L +S +, L −S +, L +S −, where + or − indicates the presence or absence of light (L) or laboratory noise (S). Light exposure was necessary to establish lateralization of attack and copulation, sound was not since only the L +S + and L +S − groups were lateralized. The lateralization of auditory habituation was not affected by these incubating conditions. Further experiments established that on day 19 of incubation exposure for 4 h to a light of constant intensity produced lateralization. 1 h exposure to a light of constant intensity or to a flickering light (1.7 Hz) failed to produce lateralization. Examination of the data for individuals suggests that light exposure synchronizes the direction of lateralization rather than generates its presence. Environmental and genetic factors interact to produce the lateralization of attack and copulation.

Interocular transfer in albino rats as a function of forebrain or forebrain plus midbrain commissurotomy

An attempt was made to determine whether interocular transfer of a black-white discrimination would be blocked by section of interhemispheric pathways. Thirty-six albino rats were equally divided into three surgical treatment groups: sham-operate, corpus callosum-section, or corpus callosum-plus superior colliculus- and posterior commissure-section. Before statistical analyses of the behavioral data were performed, the animals were reassigned to appropriate groups based upon histological examination of the lesions. The multiple-commissurotomized animals showed nearly complete incidental section of hippocampal and habenular commissures, while the callosal-sectioned and sham-operated animals had comparatively little incidental damage. The callosal-sectioned and sham-operated animals exhibited interocular transfer of a black-white discrimination, although the callosal-sectioned animals showed less transfer than the sham operates. The multiple-commissurotomized animals showed no transfer; they also made reliably more errors during acquisition via the second eye (i.e., during the test for transfer) than either the sham operates or corpus callosal-sectioned animals. These results are comparable to previous research on cats. In addition, there were no differences in the initial rates of acquisition of the black-white discrimination between the three groups; these data suggest that section of the commissures does not impair the normal mechanisms needed to acquire the discrimination.

Lateralisation of function in the chicken fore-brain

There is lateralisation of function in the chicken fore-brain. This was revealed by examining the behavioral modifications produced by administration of cycloheximide into the left or right hemisphere on Day 2 of post-hatched life. Visual discrimination learning of a task requiring a search for food was found to be performed either entirely or, at least, to a greater extent by the left hemisphere. Visual habituation learning was not found to be lateralised. The left hemisphere is more involved in auditory habituation than is the right; administration of cycloheximide to the left hemisphere slowed auditory habituation, as did bilateral administration, but treatment of the right hemisphere was ineffective. There are indications that the right hemisphere plays a more important role in response to novelty. A side-preference for response to stimuli seen by the left eye was demonstrated. These results are discussed with reference to head orientation during development in the egg.