The role of the cerebellum in schizophrenia: from cognition to molecular pathways

Beside its role in motor coordination, the cerebellum is involved in cognitive function such as attention, working memory, verbal learning, and sensory discrimination. In schizophrenia, a disturbed prefronto-thalamo-cerebellar circuit has been proposed to play a role in the pathophysiology. In addition, a deficit in the glutamatergic N-methyl-D-aspartate (NMDAf) receptor has been hypothesized. The risk gene neuregulin 1 may play a major role in this process. We demonstrated a higher expression of the NMDA receptor subunit 2D in the right cerebellar regions of schizophrenia patients, which may be a secondary upregulation due to a dysfunctional receptor. In contrast, the neuregulin 1 risk variant containing at least one C-allele was associated with decreased expression of NMDA receptor subunit 2C, leading to a dysfunction of the NMDA receptor, which in turn may lead to a dysfunction of the gamma amino butyric acid (GABA) system. Accordingly, from post-mortem studies, there is accumulating evidence that GABAergic signaling is decreased in the cerebellum of schizophrenia patients. As patients in these studies are treated with antipsychotics long term, we evaluated the effect of long-term haloperidol and clozapine treatment in an animal model. We showed that clozapine may be superior to haloperidol in restoring a deficit in NMDA receptor subunit 2C expression in the cerebellum. We discuss the molecular findings in the light of the role of the cerebellum in attention and cognitive deficits in schizophrenia.     

Effects of early onset brain injury on the development of cognition and behavior: introduction to the special issue

The effects of brain injury acquired early in life on the development of cognition and behavior are not well understood. Deciphering these effects and modeling their neurodevelopmental trajectories are major concerns for clinicians and scientists. Historically, a prevailing notion has been that early-onset brain damage has a more favorable prognosis than does brain damage acquired in adulthood. However, there is growing evidence suggesting that early-onset damage to prefrontal brain structures may have devastating consequences on the emergence of adaptive behavior throughout development. Particularly prominent are disorders of personality, social behavior, and executive functions such as planning and decision making. This special issue presents a series of new empirical studies that address these issues in depth, from several different perspectives, and in both human and animal participants. The findings promise to shed further light on both the neurobiology of development, and diverse neurodevelopmental disorders. Such advances may also enhance clinical diagnosis and facilitate the design of more effective interventions to help reduce the tremendous burden that neurodevelopmental disorders place on personal well-being, family structure, educational systems, and social resources.     

Conditioned and unconditioned forelimb reflex systems in the cat: involvement of the intermediate cerebellum

 Temporary inactivation of the cerebellar interposed nuclei was used to assess the role of the intermediate cerebellum in the performance of forelimb cutaneo-muscular reflexes in the cat. The following types of reflexive responses were evaluated: the classically conditioned and unconditioned forelimb withdrawal responses and the forelimb tactile placing, hopping and magnet responses. The experiments tested the hypothesis that the intermediate cerebellum is involved in the performance of all the above forelimb reflexes. The forelimb withdrawal reflex was classically conditioned in a newly developed paradigm in which animals were first operantly conditioned to stand on four elevated platforms. Trained animals were microinjected with a γ-aminobutyric acid (GABA) agonist, muscimol, in the interposed nuclei, and the effects of inactivation of the intermediate cerebellar output on the forelimb reflexes were examined. The main findings of these experiments are that unilateral muscimol inactivation of the interposed nuclei in the cat abolished the expression of the classically conditioned limb flexion reflex, suppressed the performance of the unconditioned withdrawal reflex and, in parallel, downregulated the tactile placing, hopping and magnet postural responses in the ipsilateral forelimb. These observations are inconsistent with concepts indicating exclusive involvement of the intermediate cerebellum in the classically conditioned reflexes elicited by aversive stimuli. On the contrary, they support the hypothesis of a more global involvement of this structure in learned and unlearned defensive flexion reflexes and in automatic postural response systems. Received: 29 July 1996 / Accepted: 26 September 1996     

Arterial stiffness,the brain and cognition: A systematic review

BackgroundArterial stiffness is a known predictor of cardiovascular disease, and has also been associated with markers of cerebral small vessel disease as well as poor cognitive function and cognitive decline. The consistency of these associations and their relationship to each other are unclear.MethodWe conducted a systematic review of the evidence associating arterial stiffness with cognitive function and cognitive decline, and with makers of cerebral small vessel disease, specifically lacunar infarcts and white matter hyperintensities.ResultsThirteen cross-sectional studies examining arterial stiffness and white matter hyperintensities or lacunar infarctions reported a positive association between increased arterial stiffness and radiological findings of cerebral small vessel disease. Two longitudinal studies examining the relationship between arterial stiffness and white matter hyperintensities found increased pulse wave velocity to be an independent predictor of white matter hyperintensity volume. Fifteen cross-sectional and seven longitudinal studies examining arterial stiffness and cognition were identified. Fourteen of the fifteen cross-sectional studies associated increased arterial stiffness with lower cognitive function, and six of the seven longitudinal studies found arterial stiffness to be predictive of cognitive decline.ConclusionArterial stiffness is associated with cerebral small vessel disease and decreased cognitive function. However methodological limitations such as differing covariates between studies and an over-reliance on the MMSE to measure cognition are a concern across much of the literature.     

Effects of estrogens on the testis of transsexuals: A pathological and immunocytochemical study

Summary Testes from five male-to-female transsexuals removed during sex-reversal surgery after administration of estrogens were studied histologically and with immunoperoxidase procedures to locate estrogen receptors (ER) and related antigens. Atrophy of the seminiferous tubules was observed in all cases; its degree, and a marked decrease in Leydig cells, correlated with low plasma gonadotropin levels (rather than with the duration of treatment). In all cases, the rete testis appeared hyperplastic and the other components (efferent ductules, epididymus) well preserved. The efferent ductules proved to be the only structure where ER can be located by the ER-ICA procedure, whereas staining for the p 29 ER-associated antigen is strongly positive both here and in the rete testis. The immunocytochemical data, in parallel with the observed biological effects, indicate that the rete testis and the efferent ductules and, to a minor degree, the epididymus and Leydig cells are the main direct targets of estrogens in the human testis.     

Prenatal and postnatal hormone effects on the human brain and cognition

This review examines the role of hormones in the development of social and nonsocial cognition and the brain. Research findings from human studies designed to elucidate the effects of both prenatal and postnatal exposure to hormones in children and young adults are summarized. Effects are found to be both time and dose dependent, with exposure to abnormal hormone levels having a limited impact outside the “critical window” in development. Particular attention is given to the role of prenatal hormone exposure, which appears to be vital for early organization of the brain. In later life, measurements of circulating hormone levels and the administration of testosterone and oxytocin are found to predict behavior, but the effect is thought to be one of “activation” or “fine-tuning” of the early organization of the brain. Possible directions for valuable future research are discussed.     

Effects of chronic neonatal nicotine exposure on nicotinic acetylcholine receptor binding, cell death and morphology in hippocampus and cerebellum

Nicotine, the major psychoactive ingredient in tobacco interacting with nicotinic acetylcholine receptors (nAChR), is believed to have neuroprotective and neurotoxic effects on the developing brain. Neurotoxicity has been attributed to activation of homomeric alpha7 nAChRs, neuroprotection to heteromeric alpha4beta2 nAChRs. Thus, developmental nicotine could have opposite effects in different brain regions, depending on nAChR subtype expression. Here, we determined if chronic neonatal nicotine exposure (CNN), during a period of brain growth corresponding to the third human trimester, differentially regulates nAChR expression, cell death, and morphological properties in hippocampus and cerebellum, two structures maturing postnatally. Rat pups were orally treated with 6 mg/kg/day nicotine from postnatal day (P)1 to P7. On P8, expression for alpha4, alpha7 and beta2 mRNA was determined by in situ hybridization; nAChR binding sites by receptor autoradiography, dying neurons by TUNEL and Fluoro-Jade staining and morphological properties by analysis of Cresyl Violet-stained sections. In control cerebellum, strong expression of alpha4, beta2 mRNA and heteromeric nAChRs labeled with [125I]-epibatidine was found in granule cells, and alpha7 mRNA and homomeric nAChRs labeled with [125I]-alpha-bungarotoxin were in the external germinal layer. In control hippocampus, low expression of alpha4 mRNA and heteromeric nAChRs and high expression of alpha7 mRNA and homomeric nAChRs were detected. CNN increased heteromeric nAChR binding in hippocampus but not cerebellum and significantly decreased neuronal soma size and increased packing density in hippocampal principal cells but not in cerebellum. CNN did not increase the number of dying cells in any area, but significantly fewer TUNEL-labeled cells were found in CA3 strata oriens and radiatum and cerebellar granule layer. Thus, the hippocampus seems to be more sensitive than the cerebellum to CNN which could result from different nAChR subtype expression and might explain long-lasting altered cognitive functions correlated with gestational nicotine exposure due to changes in hippocampal cell morphology.     

Effects of hormone therapy on brain morphology of healthy postmenopausal women: a Voxel-based morphometry study

OBJECTIVE: Estrogens are known to be protective in age-associated cognitive changes in humans and in neurodegeneration in animal models. The aim of this study was to evaluate the potential effects of estrogen therapy (ET) on human gray matter volume in vivo. DESIGN: Forty healthy postmenopausal women underwent three-dimensional high-resolution magnetic resonance imaging: 17 were never treated, 16 were currently receiving ET, and 7 had had ET in the past. Voxel-based morphometry (VBM) with SPM2 was used, according to an optimized protocol, to compare women under past and current ET to those never treated. Significance threshold was set at P = 0.01, corrected by false discovery rate. RESULTS: Voxel-based morphometry indicated that estrogen use was associated with greater gray matter volumes in the whole group of treated women, which included the cerebellum (cluster size, Z coordinates: 5,527; 5.15; -14 -54 -10), the amygdaloid-hippocampal complex (left: 19; 3.55; -22 -4 -18; right: 45; 3.61; 16 -6 -16), and extended to the frontal, temporal, parietal, and occipital neocortex. The comparison current ET versus past ET use showed that women who underwent treatment in the past had greater volumes of gray matter compared to women under current treatment. CONCLUSIONS: ET might slow down age-related gray matter loss in postmenopausal women. The structures that exhibited greater volume in association with ET included the cerebellar and cerebral cortices and, typically involved in Alzheimer's disease, the medial temporal structures and the temporoparietal junction.     

Creutzfeldt-Jakob disease with severe involvement of cerebral white matter and cerebellum

Summary We describe a patient with Creutzfeldt-Jakob disease (CJD) of the ataxic and panencephalopathic type. Postmortem examination revealed the characteristic lesions of CJD in the grey matter and profound white matter involvement was seen with immunocytochemical techniques. Ultrastructural white matter lesions were identical to those described in experimentally transmitted CJD. There was marked loss of cerebellar granule cells with virtual disappearance of parallel fibres, but Purkinje cells were only slightly reduced. Electron microscopic studies revealed extensive degenerative changes including cytoplasmic vacuoles in both cell types. Silver methods disclosed massive impregnation of white matter and striking abnormalities of Purkinje cells consisting of hypertrophy and flattening of thick dendritic branches, reduction in the number of terminal branchlets, segmentary loss of spines and polymorphic spines. These findings show the extensive involvement of all three cerebellar cortical layers and the reactive plasticity of Purkinje cells to deafferentiation. They favour the hypothesis that demyelination represents a primary lesion of the white matter.     

Early brain insult and cognition: A comparison of malnutrition and hypothyroidism

The effects of two biological insults, hypothyroidism and malnutrition, incurred during pre- and postnatal development were compared using a newly developed test of observational learning in rats. Whereas, early hypothyroidism produced a significant impairment in observational learning in recovered rats, no indication of any impairment was observed in rats recovered from early malnutrition. These results are important in that they demonstrate that tests of advantageous learning such as observational learning are sensitive to the kinds of early biological insult that lead to permanent cognitive impairment in humans. Moreover, these data further support the concept that the cognitive impairment observed during periods of malnutrition in humans and animals is not permanent.     

Social cognition, brain networks and schizophrenia

BACKGROUND: A better understanding of the neural basis of social cognition including mindreading (or theory of mind) and empathy might help to explain some deficits in social functioning in people with schizophrenia. Our aim was to review neuroimaging and neuropsychological studies on social cognition, as they may shed light on the neural mechanisms of social cognition and its dysfunction in patients with schizophrenia. METHOD: A selective literature review was undertaken. RESULTS: Neuroimaging and neuropsychological studies suggest convergence upon specific networks for mindreading and empathy (the temporal cortex, amygdala and the prefrontal cortex). The frontal lobe is likely to play a central role in enabling social cognition, but mindreading and empathic abilities may require relatively different weighting of subcomponents within the same frontal-temporal social cognition network. CONCLUSIONS: Disturbances in social cognition may represent an abnormal interaction between frontal lobe and its functionally connected cortical and subcortical areas. Future studies should seek to explore the heterogeneity of social dysfunction within schizophrenia.     

Effects of estrogens on pituitary cell and pituitary tumor growth

Estrogens have been known to induce PRL cell hyperplasia in the anterior pituitary of some species for many decades. Recent studies have shown variable susceptibility to estrogen-induced hyperplasia in different strains of rats. The distinction between hyperplastic pituitaries and adenomas is usually not made by most investigators in this field, although true neoplasms can usually be propagated by serial transplantation. The growth of transplantable tumors is usually inhibited by estrogen in vivo. Estrogens have a biphasic effect on pituitary cell proliferation in vitro with higher concentrations of estradiol inhibit cell growth, and lower concentrations stimulating PRL secretion. Estrogens can regulate PRL gene methylation in vivo thus affecting PRL mRNA expression. Recent studies have suggested that estrogen regulates signal transduction by stimulating protein kinase C. Estrogens also regulate specific proto-oncogenes such as c-myc and c-fos. These observations may help to explain some of the regulatory effects of estrogens on cell proliferation and tumor development.     

Juvenile play in the rat: thalamic and brain stem involvement

Discrete electrolytic lesions of the parafascicular area of the thalamus (PFA) or posterior thalamic area (TP) reduced the frequency of pinning, an indicator variable for rough-and-tumble play in juvenile rats, while largely sparing motivation to play. Similar sized lesions placed within the ventrobasal thalamic area (VBT) had minimal effects on both pinning and measures of play solicitation. Lesions placed within the ventrolateral aspect of the brain stem also markedly reduced pinning, while having no effect on indices of play motivation. Although tests designed to assess the extent to which the observed play deficits may be attributable to a loss of somatic acuity proved inconclusive, the overall pattern of results were not inconsistent with positing a role for these neural areas in relaying somatic stimuli relating to playful intent.     

Effects of age on tissues and regions of the cerebrum and cerebellum.

Normal volunteers, aged 30 to 99 years, were studied with MRI. Age was related to estimated volumes of: gray matter, white matter, and CSF of the cerebrum and cerebellum; gray matter, white matter, white matter abnormality, and CSF within each cerebral lobe; and gray matter of eight subcortical structures. The results were: 1) Age-related losses in the hippocampus were significantly accelerated relative to gray matter losses elsewhere in the brain. 2) Among the cerebral lobes, the frontal lobes were disproportionately affected by cortical volume loss and increased white matter abnormality. 3) Loss of cerebral and cerebellar white matter occurred later than, but was ultimately greater than, loss of gray matter. It is estimated that between the ages of 30 and 90 volume loss averages 14% in the cerebral cortex, 35% in the hippocampus, and 26% in the cerebral white matter. Separate analyses were conducted in which genetic risk associated with the Apolipoprotein E epsilon4 allele was either overrepresented or underrepresented among elderly participants. Accelerated loss of hippocampal volume was observed with both analyses and thus does not appear to be due to the presence of at-risk subjects. MR signal alterations in the tissues of older individuals pose challenges to the validity of current methods of tissue segmentation, and should be considered in the interpretation of the results.     

Effects of estrogens and progesterone on the synaptic organization of the hypothalamic ventromedial nucleus

The majority of the studies on the actions of estrogens in the ventrolateral part of the hypothalamic ventromedial nucleus (VMNvl) concern the factors that modulate the receptive component of the feminine sexual behavior and the expression of molecular markers of neuronal activation. To further our understanding of the factors that regulate synaptic plasticity in the female VMNvl, we have examined the effects of estradiol and progesterone, and of estrogen receptor (ER) subtype selective ligands on the number of dendritic and spine synapses established by individual VMNvl neurons and on sexual behavior. In contrast to earlier studies that analyzed synapse densities, our results show that exogenous estradiol increases the number of spine as well as of dendritic synapses, irrespective of the dose and regimen of administration. They also reveal that an effective dose of estradiol administered as one single pulse induces the formation of more synapses than the same dose administered as two pulses on consecutive days. Our results further show that both ER subtypes are involved in the mediation of the synaptogenic effects of estrogens on VMNvl neurons since the administration of the selective ERα, propyl-pyrazole-triol (PPT), and ERβ, diarylpropionitrile (DPN), agonists induced a significant increase in the number of synapses that, however, was more exuberant for PPT. Despite its relevant role in feminine sexual behavior, progesterone had no synaptogenic effect in the VMNvl as no changes in synapse numbers were noticed in rats treated with progesterone alone, with estradiol followed by progesterone or with the antiprogestin mifepristone (RU486). Except for the sequential administration of estradiol and progesterone, none of the regimens was associated with lordosis response to vaginocervical stimulation. Therefore, from the sex steroids that undergo cyclic variations over the estrous cycle, only estrogens, acting through both ERα and ERβ, play a key role in the activation of the neural circuits involving the ventromedial nucleus of the hypothalamus.     

健康人大脑和小脑空间记忆认知功能的fMRI研究

本研究应用功能磁共振成像(functional magnetic resonance imaging,fMRI)技术,检测了健康人大脑和小脑参与空间记忆的认知过程。通过对10名右利手健康志愿者进行一项短时空间记忆任务作业的同时进行脑功能磁共振扫描,实验采用组块设计,任务与对照任务交替进行,数据采用SPM99软件进行数据分析和脑功能区定位。结果显示:当统计阈值设定为P<0.0001时,大脑皮层和右侧小脑一起被显著激活;大脑皮层所激活的脑区有双侧顶叶的楔前叶、顶上小叶、缘上回(BA7/40,BA:Brodma-nn Area),双侧前额上、中、下回(BA6/9/47),双侧枕叶和枕颞交界处(BA18/19/37),右侧海马回;左侧中脑黑质及被盖部也被激活。上述结果提示:小脑和大脑皮层一起参与了空间记忆的认知过程。