Basal forebrain lesions impair tactile discrimination and working memory

Rats received bilateral injections of the excitotoxin, N-methyl-D,L aspartate, which resulted in degeneration of basal forebrain cholinergic (BFC) neurons in the nucleus basalis magnocellularis. Most tests of general neurological function revealed no differences between control rats and those with BFC lesions and where differences were found they appeared to be due to hyperemotionality. Rats with BFC lesions demonstrated significant deficits in working memory, as evaluated in an 8-arm radial maze. In addition, these rats showed a severe impairment in tactile discrimination learning, an effect of BFC lesions not previously demonstrated. We propose that cholinergic deafferentation of the somatosensory cortex with consequent disruption in somatosensory information processing might account at least in part for this effect.     

Sustaining high acetylcholine levels in the frontal cortex, but not retrosplenial cortex, recovers spatial memory performance in a rodent model of diencephalic amnesia

Although the thalamus and/or mammillary bodies are the primary sites of neuropathology in cases of diencephalic amnesia such as Wernicke Korsakoff Syndrome (WKS), there is also functional deactivation of certain cortical regions that contribute to the cognitive dysfunction. Acetylcholine (ACh) is a key neurotransmitter that modulates neural processing within the cortex and between the thalamus and cortex. In the pyrithiamine-induced thiamine deficiency (PTD) rat model of WKS, there are significant reductions in cholinergic innervation and behaviorally stimulated ACh efflux in the frontal (FC) and retrosplenial (RSC) cortices. In the present study, ACh released levels were site-specifically amplified with physostigmine (0.5 μg, 1.0 μg) in the FC and the RSC, which was confirmed with in vivo microdialysis. Although physostigmine sustained high ACh levels in both cortical regions, the effects on spatial memory, assessed by spontaneous alternation, were different as a function of region (FC, RSC) and treatment (PTD, pair-fed [PF]). Higher ACh levels in the FC recovered the rate of alternation in PTD rats as well as reduced arm-reentry perseverative errors. However, higher ACh levels within the FC of PF rats exacerbated arm-reentry perseverative errors without significantly affecting alternation rates. Maintaining high ACh levels in the RSC had no procognitive effects in PTD rats, but rather impaired alternation behavior in PF rats. These results demonstrate that diverse cortical regions respond differently to intensified ACh levels-and the effects are dependent on thalamic pathology. Thus, pharmacotherapeutics aimed at enhancing cognitive functions must account for the unique features of cortical ACh stimulation and the connective circuitry with the thalamus.     

Basal forebrain neurons and memory: a biochemical, histological, and behavioral study of differential vulnerability to ibotenate and quisqualate.

The differential vulnerability of basal forebrain cells to ibotenate (IBO) or quisqualate (QUIS) was investigated in rats. IBO was also coinjected with cystine (CYS) or zinc (Zn). Cortical choline acetyltransferase (ChAT) and glutamate decarboxylase (GAD) activity, neurotensin receptors, and high-affinity choline uptake sites were quantified in conjunction with radioimmunoassays for neurotensin, substance P, and somatostatin; immunocytochemistry for neurotensin-, somatostatin-, Leu-enkephalin-, and ChAT-positive cells; and in situ hybridization histochemistry of somatostatin, substance P, and enkephalin mRNAs. Compared with the performance of controls, continuous alternation performance in a T maze of IBO+Zn or IBO+CYS rats was better than that of IBO rats, whereas the performance of QUIS rats was unimpaired. Of those neurotransmitter systems examined, only ChAT-immunoreactive cells were vulnerable to IBO or QUIS. However, cholinergic cell loss did not correlate with impaired performance.     

Cholinergic system and memory in the rat: effects of chronic ethanol, embryonic basal forebrain brain transplants and excitotoxic lesions of cholinergic basal forebrain projection system

Oral administration of ethanol (20% v/v) to male Sprague-Dawley rats for different periods of time up to 28 weeks resulted in profound reductions of acetylcholine content, in vitro synthesis and release of acetylcholine, choline uptake, activities of choline acetyltransferase, acetylcholinesterase and pyruvate decarboxylase, content of noradrenaline, serotonin and, to a lesser extent, dopamine throughout the brain. Changes were fully and partially reversible by a 4 weeks' ethanol-free period following a treatment of 8 and 18 weeks, respectively. They remained persistent, however, after 28 weeks of treatment. Performance in an eight arm-radial maze revealed a severe impairment in both spatial and non-spatial reference and working memory. A similar pattern of memory impairment was obtained after ibotenate lesion of the cholinergic basal forebrain projection system. In order to test whether this memory impairment depends on cholinergic deafferentation of the cortex, cholinergic-rich fetal basal forebrain cell suspensions were transplanted into cortex, hippocampus or both these sites in ethanol treated rats. Cholinergic-rich transplants, but not cholinergic-poor transplants, were effective in ameliorating impaired memory function and measures of cholinergic activity in the basal forebrain projection system. The behavioural efficacy of the basal forebrain grafts was well correlated with measures of both transplant volume and the degree to which they restored acetylcholine content at the transplant site; these transplants had no effect, however, on brain monoamine levels. The effects of the cholinergic-rich transplants into cortical and hippocampal sites were additive in their amelioration of performance in the radial maze. Similarly, ibotenate lesions of the sites of origin of the cholinergic projections to neocortex (in the region of the nucleus basalis magnocellularis) and hippocampus (the medial septal areas and nucleus of the diagonal band), respectively, were additive in their deleterious effects on maze performance. There were no qualitative differences in the susceptibility of the four different types of memory performance measured (spatial and non-spatial reference and working memory) to the effects of ethanol, ibotenate lesions of the cholinergic projection system, or cholinergic-rich brain tissue transplants. Thus, overall, the results indicate that the forebrain cholinergic system acts as a whole, without major functional differences between the projections originating in the medial septal area/diagonal band complex and the basal nucleus, and that it discharges a very general function in cognitive processes.(ABSTRACT TRUNCATED AT 400 WORDS)     

A case of bilateral thalamic lesions with anterograde amnesia and impaired implicit memory.

Thalamic nuclei appear to play an important role in memory functioning. Severe anterograde amnesia has been reported with lesions of the dorsomedial and anterior nuclei and their connections. We report the case of a woman with discrete thalamic lesions involving the anterior and dorsomedial nuclei who had a persistent anterograde amnesia. Contrary to a previous case report describing impairment only with explicit memory, this patient had impairment with both implicit and explicit memory. This case is discussed in terms of the relevant literature associating the diencephalon, amnesia, and implicit memory.     

Cue-dependent amnesia: permanence and memory return.

Rats were trained in an appetitive maze task. In the first experiment ECS was administered in the maze start box, goal box, or a neutral box 7 days atter criterion performance. Amnesia was selective only to animals given ECS in the maze start box. No spontaneous recovery of memory was observed. In the second experiment an amnesia was created in the maze goal box by first allowing the animals to run through the maze before administering ECS in the goal box. Some evidence was presented that a second treatment with ECS may produce a return of memory.     

Intestinal parasites may not cause nosocomial infections in psychiatric hospitals

This study was conducted to determine whether nosocomial infections of intestinal parasites occur in psychiatric hospitals. Three fecal specimens were collected from each institutionalized patient in seven psychiatric hospitals of north Taiwan. Saline wet mounts were prepared to examine trophozoites, and the other parasite stages were detected using the formalin-ethyl acetate sedimentation technique. Hospital faculties were asked to complete a questionnaire on the demographic data, health status degree of disability, and recent occurrence of gastrointestinal distress of these patients. Of the 464 patients examined, 8.4% were found to be infected with one or more intestinal parasite species: 6.3% single infections, 1.5% double infections, and 0.6% triple infections. Significantly higher prevalences were found among the males, unmarried patients, those with lower education, institutionalized for more than 3 years, sent by social workers to the hospitals, with non-schizophrenic diseases, and with a higher degree of disability. However, only education, marriage, mode of hospitalization, and type of psychiatric disease were found to be significant determinants in a logistic regression model. The variation in prevalence related to demographic factors implies that nosocomial infections may not occur. The mode of hospitalization indicates that the patients may acquire the infections before hospitalization.     

Basal forebrain cholinergic lesions reduce heat shock protein 72 response but not pathology induced by the NMDA antagonist MK-801 in the rat cingulate cortex

Non-competitive N-methyl-D-aspartate (NMDA) antagonists, in addition to their neuroprotective potential, possess neurotoxic properties and induce seizures and psychosis. MK-801 induces cytoplasmic vacuoles and heat shock protein in pyramidal neurones in the rodent posterior cingulate and retrosplenial cortex. The mechanism of this neurotoxicity is unclear, involving many neurotransmitter systems. The aim of this study was to investigate the role of cholinergic pathways from the nucleus basalis of Meynert in mediating MK-801-induced neurotoxicity. Cholinergic projections from the nucleus basalis of Meynert were lesioned by focal injection of 192-IgG-saporin (80 ng), which after 7 days reduced the number of cholinergic cell bodies by 70% in the lesioned nucleus compared to the uninjected nucleus. Following a unilateral cholinergic lesion, MK-801 (5 mg/kg s.c.) induced expression of hsp72 mRNA (6 h) and HSP72 protein immunoreactivity (24 h) was reduced by 42 and 60%, respectively in the ipsilateral compared to the contralateral posterior cingulate. Despite this apparent protective effect, the unilateral cholinergic lesion did not affect the degree of neuronal vacuolation (6 h), necrosis (24 h) or the large and prolonged increase in cerebral blood flow which occurred over the first 9h following MK-801 administration. These results demonstrate that cholinergic neurones in the nucleus basalis of Meynert play an important role in the heat shock response to NMDA antagonist-induced neurotoxicity but also reveal an unexpected divergence between the heat shock response and the pathophysiological response. This suggests that other cholinergic pathways or non-cholinergic mechanisms are responsible for the pathological changes induced by MK-801.     

Transient impairment of recognition memory following ibotenic-acid lesions of the basal forebrain in macaques

Summary To assess the contributions of the basal forebrain cholinergic nuclei to visual recognition memory in macaques, we compared the effects of lesions of (a) the nucleus basalis of Meynert, (b) the medial septal and diagonal band nuclei, and (c) all nuclei combined on performance of delayed nonmatching-to-sample with trial-unique stimuli. Whereas monkeys with the separate lesions did not differ from each other or from normal control animals, those with combined lesions showed a significant impairment. With time and extended practice, however, the performance of the animals with combined lesions recovered to normal levels. During the recovery period, these monkeys showed an initially increased sensitivity to scopolamine that later dissipated, at which time they also failed to show the improvement that follows physostigmine administration in normal animals. Postmortem assessment of cortical choline acetyltransferase activity revealed that only the group with combined lesions had significant depletion of this enzyme. The results suggest that (1) the basal forebrain cholinergic system participates in mnemonic processes in primates and that (2) extensive damage to this system is necessary before impairments in recognition memory, even transient ones, can be observed.     

Medial temporal lesions in monkeys impair memory on a variety of tasks sensitive to human amnesia

Monkeys with conjoint bilateral lesions of the hippocampus and amygdala were impaired on four different tests of memory (delayed retention of object discriminations, concurrent discrimination, delayed response, and delayed nonmatching to sample). Because tests involving delays and distractions are known to be especially sensitive to human amnesia, in three of the tasks relatively long delay intervals between training and test trials were used, and in two tasks distraction was introduced during the delay intervals. The severity of the impairment increased with the length of the delay, and distraction markedly increased the memory impairment. For one task given on two occasions (delayed nonmatching to sample), the severity of the impairment was unchanged over a period of 1.5 years. Taken together with previous findings that skill learning is unimpaired in the same operated monkeys, the results of the present study strengthen the conclusion that monkeys with medial temporal lesions constitute an animal model of human amnesia. In addition, the four tasks used here appear to constitute a sensitive and appropriate battery that could be used in other studies of the neuroanatomy of memory functions in the monkey.     

Basal forebrain infusion of HC-3 in rats: maze learning deficits and neuropathology

Ten adult male Sprague-Dawley rats were infused with hemicholinium (HC-3) using mini-osmotic pumps over a 14 day period through bilateral, chronically implanted cannulae in the nucleus basalis magnocellularis (nbm). Ten matched controls were infused in the same fashion with saline. HC-3 rats receiving implants demonstrated a significant deficit in maze-learning ability compared with individual and group performances before receiving the implants. In saline rats there was no significant difference in maze-learning ability before and after receiving implants. The HC-3 group receiving implants demonstrated a significant deficit in maze-learning ability compared with the saline control group. Serial sections through nbm from control and HC-3 rats indicated that all cannulae were located within infusion range of nbm. In HC-3 subjects, cholinergic cell bodies were destroyed with concurrent degeneration of terminal fields in cortex. Except for cannula insertion damage, the cholinergic neurotransmitter system appeared unharmed in controls. Stains for neuritic plaques and neurofibrillary damage were negative in both groups. The memory deficit in experimental subjects supported by the demonstrated destruction of nbm cholinergic neurons suggests that HC-3 may be useful in the development of an animal model for Alzheimer's Disease.     

Perceptual speed does not cause intelligence, and intelligence does not cause perceptual speed

There is ongoing debate whether the efficiency of local cognitive processes leads to global cognitive ability or whether global ability feeds the efficiency of basic processes. A prominent example is the well-replicated association between inspection time (IT), a measure of perceptual discrimination speed, and intelligence (IQ), where it is not known whether increased speed is a cause or consequence of high IQ. We investigated the direction of causation between IT and IQ in 2012 genetically related subjects from Australia and The Netherlands. Models in which the reliable variance of each observed variable was specified as a latent trait showed IT correlations of -0.44 and -0.33 with respective Performance and Verbal IQ; heritabilities were 57% (IT), 83% (PIQ) and 77% (VIQ). Directional causation models provided poor fits to the data, with covariation best explained by pleiotropic genes (influencing variation in both IT and IQ). This finding of a common genetic factor provides a better target for identifying genes involved in cognition than genes which are unique to specific traits.     

Smoking may cause genetic alterations at 5q22.2 approximately q23.1 in clear-cell renal cell carcinoma

The aim of this study was to examine the relationship between allelic imbalance (AI) on chromosome 5q and clinico-pathologic parameters, including cigarette smoking. We examined the AI on chromosome 5q in 119 clear-cell renal cell carcinomas (CRCC) by a fluorescent polymerase chain reaction technique using nine microsatellite markers. AI of one or more loci was found in 43 cases (36.1%). The most frequent AI was observed at chromosome 5q23.1 (D5S467), where the LOX gene is located. The minimally involved region ranged from 5q22.1 to 5q23.2, with a possible breakpoint between 5q22 and 5q22.1. Regarding the relationships between the frequency of AI and the clinico-pathologic and environmental backgrounds, smokers had a significantly higher frequency of AI of 5q22.2 approximately q22.3 (D5S471) than nonsmokers (P = 0.013). No other significant associations were found between AI of specific loci and other parameters. Our results suggest that AI at 5q plays an important role in the genesis of CRCC. In addition, smoking may cause genetic alterations at 5q22.2 approximately q23.1, where the LOX gene is located.     

Vasopressin and memory: improvement in normal short-term recall and reduction of alcohol-induced amnesia

The vasopressin analogue 1-desamino-8-D-arginine vasopressin (DDAVP) has been shown in healthy male volunteers to cause significant improvement in short-term memory and to reduce alcohol-induced amnesia. There was no significant effect upon semantic retrieval or simple reaction time. It was concluded that vasopressin benefited the initial processes of consolidation and learning, while the reduction of the amnesic effects of alcohol may support the contentions of other authors that the peptide improves memory in states of mild amnesia.     

Prolactin does not cause breast cancer and may prevent it or be therapeutic in some conditions

The polypeptide hormone prolactin (PRL), ubiquitous and multifunctional in vertebrates, always interested biologists, was of restricted concern to clinicians and researched little compared to insulin and growth hormone. PRL in lactation initially aroused relatively little interest, but it rose when with ovarian steroids and chemical carcinogens, it was implicated in rodent mammary carcinoma. It declined when PRL suppression did not counter breast cancer. Meanwhile, long-known, estrogen-related cancers in the ovary and breast did not deter wide estrogen use for contraception and supplementation despite risk, and estrogen blockers and inhibitors have improved treatment and are on trial for prophylaxis, despite serious short and long term side-effects. Despite the great differences between steroid and polypeptide, research on PRL and breast cancer mirroring that on estrogens is now growing. This is mainly negative, much due to recent prospective research reporting minor rises in plasma levels as a basis, together with some recent laboratory research, for a hypothesis that PRL induces post-menopausal breast cancer. That view contradicts a reproductive biology that evolved to benefit women and offspring. Elevated PRL in pregnancy and probably that in lactation, reduce risk. Many exogenous chemical and physical PRL-stimulants also do not increase risk. It has not been shown that PRL increases risk of breast cancer and some older and recent cell and tissue data suggest it may be the key, two-sided, in human breast tissue homeostasis. Excessive disturbance of this is unlikely to originate in PRL itself. The natural biology of PRL, the reproductive woman's hormone par excellence, and research in various fields, suggest a positive potential in the PRL family for direct prevention and treatment of breast cancer, possibly greater than that in the estrogens. It is time to debate and research this.