Time-dependent recovery of taste aversion learning by fetal brain transplants in gustatory neocortex-lesioned rats.

We recently showed that fetal brain transplants produced a significant recovery in the ability of gustatory neocortex-lesioned rats to learn a conditioned taste aversion. In this report we assessed the capability of gustatory neocortex fetal brain transplants to produce behavioral recovery at different times. Four groups of male Wistar rats showing disrupted taste aversions due to gustatory neocortex lesions were studied. The lesioned animals received fetal cortical grafts, obtained from 16-day-old fetuses, and were retrained in the behavioral procedure after 15, 30, 45, or 60 days postgraft. Behavioral results showed a very good functional recuperation at 60 days, slight recovery at 45 and 30 days, and a poor recovery at 15 days postgraft. Results with HRP histochemistry revealed that at 30, 45, and 60 days postgrafting there were increased connections with the ventromedial nucleus of the thalamus and with the amygdala. At 15 days postgrafting there was an absence of HRP-labeled cells. In addition, behavioral recovery was correlated with increased acetylcholinesterase activity, detected histochemically, and with morphological neuronal maturation, revealed by Golgi staining. These results suggest that morphological maturity and reconnectivity between grafts and host tissue are important for behavioral recovery in gustatory neocortex-lesioned rats.     

Ethical Issues in Neurografting of Human Embryonic Cells

During the last decade neurotransplantation has developed into a technique with the possible potential to repair damaged or degenerating human brain. Effective neurotransplantation has so far been based on the use of fetal brain tissue derived from aborted embryos or fetuses. The ethical issues related to this new therapeutic approach therefore not only concern the possible adverse side effects for a neural graft-receiving patient, but also the relationship between the requirements for fetal tissue and the decision-making process for induced abortion. Although for decades human embryos and fetuses have been the subject of biomedical studies, and, in principle, their use has therefore not been seen as ethically objectionable, the above points made it necessary to reconsider the moral issues. The present paper points out several of these issues, both from the donor and acceptor (patient) point of view. The conclusion is that under a series of restrictions intended to prevent the use of grafts from encouraging induced abortions and to maintain high standards of respect for life and human dignity, neurotransplantation using embryonic or fetal brain tissue parts cannot be rejected on moral grounds.     

Frontal cortex grafts have opposite effects at different postoperative recovery times

We studied the effect of different postoperative times on the behavioral recovery following brain implants. Adult male rats received cortical tissue grafts 2 weeks after aspiration of the medial frontal cortex. Either 2 (Immediate Group) or 28 (Delay Group) days after grafting, the performance of these rats on a behavioral battery, comprising the Morris water maze task, forepaw use, and grooming, was compared to that of rats with similar lesions and postoperative recovery times but no grafts. Rats tested immediately after receiving implants performed better on the spatial navigation task than rats with similar lesions but no grafts. This improvement, however, was less than that shown by rats with lesions but no grafts permitted to recover for 28 days before testing. In contrast, in the Delay Group, rats with grafts were more greatly impaired than were their operated controls. Neither lesions nor grafts affected grooming although the Immediate Group with grafts were significantly more impaired in using their forepaws during feeding than were any of the other groups. These results lead us to conclude that differing postoperative recovery times and task requirements may account for some of the inconsistent results of the influence of brain grafts on behavioral recovery reported in the literature. We also conclude that cortical tissue implants can have two effects with different time courses and opposite net behavioral effects.     

TMS in cognitive plasticity and the potential for rehabilitation

Cognitive neuroscientists use transcranial magnetic stimulation (TMS) in several ways, from aiming to increase understanding of brain-behavior relationships to transiently improving performance, both in normals and in patients with neurological and neuropsychological deficits. Different types of TMS (single-pulse, paired-pulse, repetitive) are able to interfere with higher brain functions that require the cooperation of different brain areas and complex neuronal networks. Currently, behavioral TMS effects on the brain are usually short-lived and their underlying mechanisms not yet wholly understood. However, the aim of using TMS to develop rehabilitative strategies for motor, perceptive and cognitive functions represents an intriguing challenge.     

Hippocampal deafferentation: transplantderived reinnervation and functional recovery

A brief review is provided of the capacity of neural tissue transplants to reinnervate the deafferented hippocampus and repair functional deficits induced by the lesion. The techniques for transplantation of solid pieces of embryonic septum, locus coeruleus or raphe nuclei, or tissue suspensions of embryonic septum, to the adult rat hippocampus are described. Such grafts manifest good long-term survival, provide a good reinnervation of the hippocampus that is histochemically and biochemically appropriate and specific, can establish ultrastructural synaptic contacts with the host, and are electrophysiologically active. Rats with septal grafts manifest recovery of the capacity to learn certain aspects of radial 8-arm maze, T-maze alternation and Morris water-maze tasks. Rats with locus coeruleus grafts manifest an amelioration of lesion-induced hyperactivity. It is concluded that neural tissue transplantation provides a powerful new tool in the study of the functional organization of the hippocampus and its various neurotransmitter-specific afferent systems.     

Adrenal medulla graft induced recovery of function in an animal model of Parkinson's disease: possible mechanisms of action

Following unilateral dopamine (DA) denervation of the striatum in animals, there is an asymmetry in the striatal DA system. Animals with such denervations will rotate vigorously when given dopaminergic drugs. Adrenal medulla grafts placed in the lateral ventricle adjacent to a DA-denervated striatum decrease rotational behaviour induced by DA receptor agonists or DA-releasing agents. This discussion reviews research on the use of adrenal medulla grafts to reverse behavioural deficits following DA-denervation of the striatum. Results from basic animal research and from the application of the procedure to patients with Parkinson's disease suggests that at least three different fundamental processes may mediate the functional effects of adrenal medulla grafts: (a) Adrenal medulla grafts may induce changes in the blood-brain barrier; (b) adrenal medulla grafts may induce an increase in serum DA; and (c) adrenal medulla grafts may have a trophic effect on the host brain. Hypotheses are proposed to explain the behavioural effects of adrenal medulla grafts in light of the processes that are thought to mediate their effects.     

Congenital Hypothyroidism: An Analysis of Persisting Deficits and Associated Factors

Congenital hypothyroidism (CH) is a neonatal disorder that is caused by a prolonged loss of thyroid hormone, which is essential for early brain development. While CH was once the leading cause of mental retardation, newborn screening for CH now allows for early identification and treatment. As a result, affected children now show normal physical and psychological development. Nevertheless, because they still undergo a brief but circumscribed period of thyroid hormone insufficiency, they are at risk for subtle selective impairments. This paper examines several of the persisting deficits observed in children with CH that was identified early in life by newborn screening as well as the relevant disease- and treatment-related factors contributing to such deficits. Highlighted will be (a) a weakness in visuospatial processing, which is associated with prenatal thyroid hormone insufficiency, (b) selective memory deficits associated with postnatal thyroid hormone insufficiencies, (c) a weakness in sensorimotor abilities also reflecting postnatal thyroid hormone insufficiencies, and (d) attention deficits, which are due to abnormal thyroid hormone levels at time of testing. Because these four disabilities implicate different neural substrates, the findings described presently will provide insights as to the specific time windows when different brain structures in the human critically need thyroid hormone.     

Congenital hypothyroidism: an analysis of persisting deficits and associated factors.

Congenital hypothyroidism (CH) is a neonatal disorder that is caused by a prolonged loss of thyroid hormone, which is essential for early brain development. While CH was once the leading cause of mental retardation, newborn screening for CH now allows for early identification and treatment. As a result, affected children now show normal physical and psychological development. Nevertheless, because they still undergo a brief but circumscribed period of thyroid hormone insufficiency, they are at risk for subtle selective impairments. This paper examines several of the persisting deficits observed in children with CH that was identified early in life by newborn screening as well as the relevant disease- and treatment-related factors contributing to such deficits. Highlighted will be (a) a weakness in visuospatial processing, which is associated with prenatal thyroid hormone insufficiency, (b) selective memory deficits associated with postnatal thyroid hormone insufficiencies, (c) a weakness in sensorimotor abilities also reflecting postnatal thyroid hormone insufficiencies, and (d) attention deficits, which are due to abnormal thyroid hormone levels at time of testing. Because these four disabilities implicate different neural substrates, the findings described presently will provide insights as to the specific time windows when different brain structures in the human critically need thyroid hormone.     

Functional effects of neural grafting in the mammalian central nervous system

Grafts of fetal and nonfetal brain tissues have been successfully implanted into the mammalian central nervous system (CNS). The functional effects of neural grafting in the CNS of rodents and nonhuman primates in a variety of situations are reviewed. Research areas discussed included the effects of dopamine-rich grafts in animal models of Parkinson's disease and acetylcholine-rich grafts in animals with lesions of the cholinergic pathways to the neocortex and hippocampus. Graft effects also are examined in aged animals and genetic mutants. In addition, the effects of neural grafts on circadian rhythmicity, reproductive functions, and conditioned taste aversion are discussed. The beneficial functional effects of neural grafts and the possible mechanisms and implications for these effects are discussed, including the possibility that the CNS exhibits a regional biochemical specificity that influences the outcome of neural graft procedures.     

Attenuation of Morphine-Induced Behavioral Changes in Rodents byd-andl-Glucose

Administration ofd-glucose enhances learning and memory in several tasks and also attenuates memory impairments and other behavioral effects of several drugs, including morphine. The present experiment compared the effects of peripherally administeredd-glucose with those ofl-glucose, a stereoisomer ofd-glucose that is not metabolized and does not readily cross the blood–brain barrier. Liked-glucose, though at somewhat different doses, peripherally administeredl-glucose attenuated morphine-induced deficits in spontaneous alternation performance in rats and mice and attenuated morphine-induced hyperactivity in mice.l-Glucose did not raise circulating levels of plasmad-glucose, suggesting that the effects ofl-glucose are not secondary to increased availability ofd-glucose. Using direct injections ofd- andl-glucose and morphine into the medial septum of rats, the findings indicate thatd-glucose but notl-glucose attenuated morphine-induced deficits in spontaneous alternation performance; indeed, intraseptal injections ofl-glucose alone impaired spontaneous alternation performance. These findings suggest that peripherall-glucose antagonizes morphine-induced behavioral effects by a peripheral signaling mechanism, one distinct from the mechanisms that mediate at least some of the effects ofd-glucose on brain function.     

Cerebral perfusion in chronic stroke: implications for lesion-symptom mapping and functional MRI

Lesion-symptom mapping studies are based upon the assumption that behavioral impairments are directly related to structural brain damage. Given what is known about the relationship between perfusion deficits and impairment in acute stroke, attributing specific behavioral impairments to localized brain damage leaves much room for speculation, as impairments could also reflect abnormal neurovascular function in brain regions that appear structurally intact on traditional CT and MRI scans. Compared to acute stroke, the understanding of cerebral perfusion in chronic stroke is far less clear. Utilizing arterial spin labeling (ASL) MRI, we examined perfusion in 17 patients with chronic left hemisphere stroke. The results revealed a decrease in left hemisphere perfusion, primarily in peri-infarct tissue. There was also a strong relationship between increased infarct size and decreased perfusion. These findings have implications for lesion-symptom mapping studies as well as research that relies on functional MRI to study chronic stroke.     

胚胎期可卡因、吗啡暴露影响子代成瘾相关行为的神经发育机制

孕期使用毒品可影响胎儿大脑的正常发育,导致脑内神经递质系统异常以及行为的改变.近年来不断有研究证据提示,胚胎期接触可卡因、吗啡等成瘾药物,可以影响神经细胞的增殖、迁移或凋亡等发育过程,使中脑皮层边缘系统中多巴胺、GABA、谷氨酸等神经元形态、受体功能以及突触可塑性发生改变,从而导致子代的学习记忆和成瘾易感性等行为异常.本文将从行为、神经发育、递质系统以及脑功能等层面归纳胚胎期用药对成瘾相关行为影响机制的重要研究进展,并试图提出可能的研究展望.     

The contribution of novel brain imaging techniques to understanding the neurobiology of mental retardation and developmental disabilities

Studying the biological mechanisms underlying mental retardation and developmental disabilities (MR/DD) is a very complex task. This is due to the wide heterogeneity of etiologies and pathways that lead to MR/DD. Breakthroughs in genetics and molecular biology and the development of sophisticated brain imaging techniques during the last decades have facilitated the emergence of a field called Behavioral Neurogenetics. Behavioral Neurogenetics focuses on studying genetic diseases with known etiologies that are manifested by unique cognitive and behavioral phenotypes. In this review, we describe the principles of magnetic resonance imaging (MRI) techniques, including structural MRI, functional MRI, and diffusion tensor imaging (DTI), and how they are implemented in the study of Williams (WS), velocardiofacial (VCFS), and fragile X (FXS) syndromes. From WS we learn that dorsal stream abnormalities can be associated with visuospatial deficits; VCFS is a model for exploring the molecular and brain pathways that lead to psychiatric disorders for which subjects with MR/DD are at increased risk; and finally, findings from multimodal imaging techniques show that aberrant frontal-striatal connections are implicated in the executive function and attentional deficits of subjects with FXS. By deciphering the molecular pathways and brain structure and function associated with cognitive deficits, we will gain a better understanding of the pathophysiology of MR/DD, which will eventually make possible more specific treatments for this population.     

Effects of aging on the neural correlates of successful item and source memory encoding

To investigate the neural basis of age-related source memory (SM) deficits, young and older adults were scanned with fMRI while encoding faces, scenes, and face-scene pairs. Successful encoding activity was identified by comparing encoding activity for subsequently remembered versus forgotten items or pairs. Age deficits in successful encoding activity in hippocampal and prefrontal regions were more pronounced for SM (pairs) as compared with item memory (faces and scenes). Age-related reductions were also found in regions specialized in processing faces (fusiform face area) and scenes (parahippocampal place area), but these reductions were similar for item and SM. Functional connectivity between the hippocampus and the rest of the brain was also affected by aging; whereas connections with posterior cortices were weaker in older adults, connections with anterior cortices, including prefrontal regions, were stronger in older adults. Taken together, the results provide a link between SM deficits in older adults and reduced recruitment of hippocampal and prefrontal regions during encoding. The functional connectivity findings are consistent with a posterior-anterior shift with aging previously reported in several cognitive domains and linked to functional compensation.     

Neuroanatomical substrates of social cognition dysfunction in autism

In this review article, we summarize recent progress toward understanding the neural structures and circuitry underlying dysfunctional social cognition in autism. We review selected studies from the growing literature that has used the functional neuroimaging techniques of cognitive neuroscience to map out the neuroanatomical substrates of social cognition in autism. We also draw upon functional neuroimaging studies with neurologically normal individuals and individuals with brain lesions to highlight the insights these studies offer that may help elucidate the search for the neural basis of social cognition deficits in autism. We organize this review around key brain structures that have been implicated in the social cognition deficits in autism: (1) the amygdala, (2) the superior temporal sulcus region, and (3) the fusiform gyrus. We review some of what is known about the contribution of each structure to social cognition and then review autism studies that implicate that particular structure. We conclude with a discussion of several potential future directions in the cognitive neuroscience of social deficits in autism.     

Fetal Alcohol Spectrum Disorders: Neuropsychological and Behavioral Features

Heavy prenatal alcohol exposure can cause alterations to the developing brain. The resulting neurobehavioral deficits seen following this exposure are wide-ranging and potentially devastating and, therefore, are of significant concern to individuals, families, communities, and society. These effects occur on a continuum, and qualitatively similar neuropsychological and behavioral features are seen across the spectrum of effect. The term fetal alcohol spectrum disorders (FASD) has been used to emphasize the continuous nature of the outcomes of prenatal alcohol exposure, with fetal alcohol syndrome (FAS) representing one point on the spectrum. This paper will provide a comprehensive review of the neuropsychological and behavioral effects of heavy prenatal alcohol exposure, including a discussion of the emerging neurobehavioral profile. Supporting studies of lower levels of exposure, brain-behavior associations, and animal model systems will be included when appropriate.     

Neuropsychological profiles of six children with anoxic brain injury

Anoxic brain injury (ABI) often results in severe memory impairment and other cognitive and behavioral deficits, although limited information is available regarding pediatric cases. This study reported the neuropsychological outcomes in six children and adolescents who sustained ABI. Profiles were compared by mechanism of injury (ischemic vs. hypoxemic) and three cases were evaluated more than once. Severe intellectual, attention, memory, and behavioral impairments were observed in all six cases although academic achievement, internalizing behavioral problems, and visuospatial deficits were in general less severe than other cognitive and behavioral deficits. The longitudinal case studies varied but showed steady increases in memory and intellectual performance in the younger children with strongest improvement in nonverbal abilities and little change in parent-reported behavior. This study raises several possible hypotheses about specific cognitive and behavioral outcomes observed in pediatric ABI.     

Cognitive and Emotional Abnormalities in Systemic Lupus Erythematosus: Evidence for Amygdala Dysfunction

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disorder characterized by the production of autoantibodies. Approximately 30-50?% of patients produce autoantibodies directed against N-Methyl-D-aspartic acid receptors (NMDARs). Once they have gained access to brain tissue, these autoantibodies bind to the NR2A subunit of the NMDARs and synergize with glutamate to cause excitatory, non-inflammatory cell death or alter neuron function. Both humans with SLE and animal models of SLE have shown structural and functional damage to the amygdala. The amygdala is a brain region important for processing the emotional relevance of stimuli in the environment. It also serves to modulate perception, attention, and memory to facilitate the processing and learning of relevant stimuli. Research has linked amygdala damage to deficits in emotional memory and emotional behavior. Individuals with SLE often exhibit emotional dysregulation, such as lability and depression; however, the behavioral impact of possible amygdala dysfunction has yet to be studied in this population. The purpose of this review is to 1) examine possible associations between SLE, anti-NMDAR antibodies, amygdala damage, and emotional processing deficits and 2) to identify the clinical, social, and treatment implications for individuals with SLE who suffer from deficits in emotional processing.     

Growth-related neural reorganization and the autism phenotype: a test of the hypothesis that altered brain growth leads to altered connectivity

Theoretical considerations, and findings from computational modeling, comparative neuroanatomy and developmental neuroscience, motivate the hypothesis that a deviant brain growth trajectory will lead to deviant patterns of change in cortico-cortical connectivity. Differences in brain size during development will alter the relative cost and effectiveness of short- and long-distance connections, and should thus impact the growth and retention of connections. Reduced brain size should favor long-distance connectivity; brain overgrowth should favor short-distance connectivity; and inconsistent deviations from the normal growth trajectory - as occurs in autism - should result in potentially disruptive changes to established patterns of functional and physical connectivity during development. To explore this hypothesis, neural networks which modeled inter-hemispheric interaction were grown at the rate of either typically developing children or children with autism. The influence of the length of the inter-hemispheric connections was analyzed at multiple developmental time-points. The networks that modeled autistic growth were less affected by removal of the inter-hemispheric connections than those that modeled normal growth - indicating a reduced reliance on long-distance connections - for short response times, and this difference increased substantially at approximately 24 simulated months of age. The performance of the networks showed a corresponding decline during development. And direct analysis of the connection weights showed a parallel reduction in connectivity. These modeling results support the hypothesis that the deviant growth trajectory in autism spectrum disorders may lead to a disruption of established patterns of functional connectivity during development, with potentially negative behavioral consequences, and a subsequent reduction in physical connectivity. The results are discussed in relation to the growing body of evidence of reduced functional and structural connectivity in autism, and in relation to the behavioral phenotype, particularly the developmental aspects.     

The organization of motivated and conditional reflex processes

Recent observations on the plasticity of brain and behavior relationships indicate that the temporary connections between environmental and neuroanatomical substrates have tremendous specificity but at the same time are very plastic. Establishment of a conditional reflex by stimulation of the hippocampal pyramidal layer and/or the mesencephalic reticular formation did not interfere with the differential stimulation of very near points in the same structures. These correlations between brain and behavior confirmed the earlier belief that the development of temporary connections between environment and brain is an elementary process of the central nervous system. Complex behavioral functions are organized through both neuronal and humoral afferentation. Data accumulated recently indicate that the descending forebrain influence is inhibitory in the brain stem and diencephalon and controls the sensory input in a somatomotor-specific and situation-specific manner. Humoral factors affecting thresholds can change the dynamic equilibrium existing between ascending excitatory and descending inhibitory systems; these alterations always follow the rule of situation and somatomotor specificity.