Region-specific Alterations Research Articles

The MPTP neurotoxic lesion model of Parkinson's disease activates the apolipoprotein E cascade in the mouse brain

Apolipoprotein E (apoE) is recognized as a key actor in brain remodeling. It has been shown to increase after peripheral and central injury, to modulate reparative capacity in neurodegenerative conditions like Alzheimer's disease (AD) and to be associated with a number of other neurodegenerative diseases. This particular function of apoE has been postulated to underlie the robust association with risk and age at onset of AD. ApoE associations studies with Parkinson's disease (PD), the second most prevalent neurodegenerative disease, have generated contradictory results but associations with age at onset and dementia in PD stand out. We investigate here whether apoE is involved in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration that models PD-like deafferentation of the striatum in the mouse and participates in compensatory reinnervation mechanisms. We examined the modifications in gene expression and protein levels of apoE and its key receptors, the low density lipoprotein receptor (LDLR) and the LDLR-related protein (LRP), as well as the reactive astrocyte marker glial fibrillary acidic protein (GFAP) in different brain structures throughout the degenerative and reactive regenerative period. In the striatum, upregulations of GFAP, apoE and LRP mRNAs at 1day post-treatment were associated with marked decreases in dopamine (DA) levels, loss in tyrosine hydroxylase protein content, as well as to a compensatory increase in dopaminergic metabolism. Subsequent return to near control levels coincided with indications of reinnervation in the striatum: all consistent with a role of apoE during the degenerative process and regenerative period. We also found that this cascade was activated in the hippocampus and more so than in the striatum, with a particular contribution of LDLR expression. The hippocampal activation did not correlate with substantial neurochemical reductions but appears to reflect local subtle alteration of DA metabolism and the regulation of plasticity-related event in this structure. This study provides first evidence of an activation of the apoE/apoE receptors cascade in a mouse model of PD, specifically in the MPTP-induced deafferentation of the striatum. Results are also quite consistent with the postulated role of apoE in brain repair but, raise the issue of possible lesion- and region-specific alterations in gene expression.

Gender-dependent behavioral and biochemical effects of adolescent delta-9-tetrahydrocannabinol in adult maternally deprived rats

Preclinical data support the long-term adverse effects on cognition, emotionality, and psychotic-like behaviors of adolescent exposure to natural and synthetic cannabinoids. To investigate whether the long-lasting adverse effects induced by cannabinoids in adolescence are influenced by early-life stress, female and male rats were subjected to 24-h maternal deprivation at postnatal day (PND) 9 and treated with tetrahydrocannabinol (THC) during adolescence (PND 35–45) according to our previously reported protocol. At adulthood, rats were tested in the novel object recognition, social interaction, and forced swim tests, to evaluate possible alterations in recognition memory, social behavior, and coping strategy. Moreover, cannabinoid CB1 receptor density and functionality, as well as NMDA and dopamine D1 and D2 receptor densities were measured through autoradiographic binding studies. In female maternally deprived rats, THC failed to impair recognition memory, counteracted aggressiveness induced by maternal deprivation, whereas no interaction was observed in the passive coping behavior. In males, the association of the two events increased passive coping response without affecting other behaviors. This behavioral picture was accompanied by gender-dependent and region-specific alterations in NMDA, D1 and D2 receptors. In conclusion, this study demonstrates that adolescent THC exposure might have different behavioral outcomes in animals previously exposed to early-life stress compared with non-stressed controls. The interaction between the two events is not univocal, and different combinations may arise depending on the sex of the animals and the behavior considered. Alterations in NMDA, D1 and D2 receptors might be involved in the behavioral responses induced by maternal deprivation and in their modulation by THC.This article is part of a Special Issue entitled: Stress, Emotional Behavior and the Endocannabinoid System.

Regional specific alterations in brain acetylcholinesterase activity after repeated blast exposures in mice

Acetylcholinesterase (AChE) which catalyzes the hydrolysis of the neurotransmitter acetylcholine has been recognized as one of the major regulators of stress responses after traumatic brain injury (TBI). Repeated blast exposure induces TBI (blast TBI) with a variable neuropathology at different brain regions. Since AChE inhibitors are being used as a line of treatment for TBI, we sought to determine the time course of AChE activity in the blood and different brain regions after repeated blast exposures using modified Ellman assay. Our data showed that repeated blast exposures significantly reduced AChE activity in the whole-blood and erythrocytes by 3–6 h, while plasma AChE activity was significantly increased by 3 h post-blast. In the brain, significant increase in AChE activity was observed at 6 h in the frontal cortex, while hind cortex and hippocampus showed a significant decrease at 6 h post-blast, which returned to normal levels by 7 days. AChE activity in the cerebellum and mid brain showed a decrease at 6 h, followed by significant increase at 3 days and that was decreased significantly at 14 days post-blast. Medulla region showed decreased AChE activity at 24 h post-blast, which was significantly increased at 14 days. These results suggest that there are brain regional and time-related changes in AChE activity after tightly coupled repeated blast exposures in mice. In summary, acute and chronic regional specific changes in the AChE activity after repeated blast exposures warrant systematic evaluation of the possibility of AChE inhibitor therapeutics against blast TBI.

Brain region‐specific gene expression changes after chronic intermittent ethanol exposure and early withdrawal in C57BL/6J mice

Neuroadaptations that participate in the ontogeny of alcohol dependence are likely a result of altered gene expression in various brain regions. The present study investigated brain region-specific changes in the pattern and magnitude of gene expression immediately following chronic intermittent ethanol (CIE) exposure and 8 hours following final ethanol exposure [i.e. early withdrawal (EWD)]. High-density oligonucleotide microarrays (Affymetrix 430A 2.0, Affymetrix, Santa Clara, CA, USA) and bioinformatics analysis were used to characterize gene expression and function in the prefrontal cortex (PFC), hippocampus (HPC) and nucleus accumbens (NAc) of C57BL/6J mice (Jackson Laboratories, Bar Harbor, ME, USA). Gene expression levels were determined using gene chip robust multi-array average followed by statistical analysis of microarrays and validated by quantitative real-time reverse transcription polymerase chain reaction and Western blot analysis. Results indicated that immediately following CIE exposure, changes in gene expression were strikingly greater in the PFC (284 genes) compared with the HPC (16 genes) and NAc (32 genes). Bioinformatics analysis revealed that most of the transcriptionally responsive genes in the PFC were involved in Ras/MAPK signaling, notch signaling or ubiquitination. In contrast, during EWD, changes in gene expression were greatest in the HPC (139 genes) compared with the PFC (four genes) and NAc (eight genes). The most transcriptionally responsive genes in the HPC were involved in mRNA processing or actin dynamics. Of the few genes detected in the NAc, the most representatives were involved in circadian rhythms. Overall, these findings indicate that brain region-specific and time-dependent neuroadaptive alterations in gene expression play an integral role in the development of alcohol dependence and withdrawal.

Endocrine and developmental effects in Atlantic salmon ( Salmo salar) exposed to perfluorooctane sulfonic or perfluorooctane carboxylic acids

In this study, we have investigated the effect of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) on endocrine signalling, growth and development in Atlantic salmon ( Salmo salar) embryos and larvae. Expression of genes related to the hypothalamic–pituitary–thyroid (HPT) axis, growth-hormone/insulin-like growth factor (GH/IGF) axis and the steroid hormone axis were used as indicators of endocrine disruption. We also studied bone development in larvae, both by observing skeletal structure formation and by investigating expression of genes involved in ossification process. Atlantic salmon embryos, kept in plastic tanks at 5–7 °C, were exposed to 100 μg/L PFOA or PFOS from egg stage for a period of 52 days, followed by one-week recovery period. Sampling was performed at day 21, 35, 49 and 56 representing age 549, 597, 679 and 721 dd (dd or day degrees = number of days × temperature in degree Celsius: °C). Note that day 56 or 721 dd is the end of the 1-week recovery period. Larvae were divided into designated head and body regions for the purpose of gene expression analysis, except for genes that regulate ossification that were analyzed in whole larvae. Expression of thyroid receptor α and β (TRα and TRβ), thyroid-stimulating hormone β (TSHβ), T 4 outer-ring deiodinase (T 4ORD), growth hormone (GH), insulin-like growth factor-I and II (IGF-I and II), insulin-like growth factor I receptor (IGF-IR), and estrogen receptor α and β (ERα and ERβ) were investigated using quantitative PCR. Both PFOS and PFOA exposure produced non-significant alterations in larvae weight (except after the recovery period when a decrease was observed), while larvae length was unaffected. PFOS and PFOA exposure produced body- and head region-specific alterations in expression of all the investigated gene transcripts. Expression of IGF-I and IGF-IR paralleled that of GH, indicating that perturbation of GH expression is a possible end point for disruption of the GH–IGF axis. We did not observe developmental changes related to angiogenesis, ossification and chondrogenesis after exposure to PFOS and PFOA. Transcriptional abnormalities may serve as indicators of chronic exposure, although the concrete mechanisms causing the observed effects remain ambiguous. The implications of these findings for the complete lifecycle, including other developmental and/or reproductive damage, are areas of future study.

Hypothalamic Dynamics of CD26 Protein in Obese and Fasted Rats

Background : Impaired control of brain functions by CD26 alterations and sensing of unbalanced metabolism could be related in obese and fasting rats. This study aims to search the hypothalamic regions targeted by the alterations of CD26 and cellular activity (Fos) in monosodium glutamate obese (MSG) and food deprived (FD) rats. Methods : The patterns of distribution of immunoreactivity (ir) of CD26 and Fos were quantified in the hypothalamus. Results : Compared to control, the CD26-ir increased in the supraoptic and retrochiasmatic nuclei of MSG. CD26-ir and Fos-ir concomitantly decreased in the dorsomedial and retrochiasmatic nuclei of MSG-FD, the paraventricular nucleus of MSG and MSG-FD and in the supraoptic nucleus of FD and MSG-FD, while they exhibited opposite changes in the retrochiasmatic nucleus of FD and MSG, the arcuate and periventricular nuclei of FD, MSG and MSG-FD, the paraventricular and dorsomedial nuclei of FD and the supraoptic nucleus of MSG. Conclusions : The data provide clear evidences for regional specific alterations of CD26 together with altered cellular activity in the hypothalamus of MSG and FD animals and demonstrate that regulation of CD26 is a hallmark of hypothalamic exposure to metabolic challenges. d oi:10.4021/jem24w

Phenotypic and gene expression modification with normal brain aging in GFAP-positive astrocytes and neural stem cells

Astrocytes secrete growth factors that are both neuroprotective and supportive for the local environment. Identified by glial fibrillary acidic protein (GFAP) expression, astrocytes exhibit heterogeneity in morphology and in the expression of phenotypic markers and growth factors throughout different adult brain regions. In adult neurogenic niches, astrocytes secrete vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) within the neurogenic niche and are also a source of special GFAP-positive multipotent neural stem cells (NSCs). Normal aging is accompanied by a decline in CNS function and reduced neurogenesis. We asked whether a decreased availability of astrocyte-derived factors may contribute to the age-related decline in neurogenesis. Determining alterations of astrocytic activity in the aging brain is crucial for understanding CNS homeostasis in aging and for assessing appropriate therapeutic targets for an aging population. We found region-specific alterations in the gene expression of GFAP, VEGF, and FGF-2 and their receptors in the aged brain corresponding to changes in astrocytic reactivity, supporting astrocytic heterogeneity and demonstrating a differential aging effect. We found that GFAP-positive NSCs uniquely coexpress both VEGF and its key mitotic receptor Flk-1 in both young and aged hippocampus, indicating a possible autocrine/paracrine signaling mechanism. VEGF expression is lost once NSCs commit to a neuronal fate, but Flk-1-mediated sensitivity to VEGF signaling is maintained. We propose that age-related astrocytic changes result in reduced VEGF and FGF-2 signaling, which in turn limits NSC and progenitor cell maintenance and contributes to decreased neurogenesis.

Associations between the behavioral psychological symptoms in Alzheimer's disease and cerebral blood flow in cerebral heteroplasia cortex

Objective To explore the relationship between behavioral psychological symptoms in Alzheimer' s dementia(AD) patients and region-specific alterations in cerebral blood flow. Methods 60 patients with AD randomly selected from a psychiatric outpatient department and 30 randomly selected healthy elderly community controls were administered the Mini-Mental State Exam (MMSE). All subjects underwent a perfusion CT scan to assess blood perfusion in brain regions of interest. The AD subjects were administered the behavioral patholigy in alzheimer' s disease(BEHAVE-AD) Rating Scale classified as mild, moderate or severe based on the results of the Clinical Dementia Rating scale. Results The most incidence was conduct disorder and the next was delusion.The score was 81.7% and 58.3% in turn. The conduct disorder score was higher in the severe demented group than in the mildly and moderate demented group(P＜0. 05). The delusion score was higher in the moderate demented group than that in the mildly demented group(P＜0.05). The time to peak(TTP)scores in the four groups of subjects were significantly different in the bilateral hippocampal formation, anteroinferior subiculum and entorhinal area. The TTP score was significantly higher in the moderately demented group than that in the mildly demented group and the control group(P＜0. 05 ). Correlation analysis identified a positive correlation between conduct disorder, delusions and TTP in cerebral heteroplasia cortex (P ＜ 0. 05 ), also identified a negative correlation between mood disorder and TTP(P＜0. 05 ). Conclusion The conduct disorder,delusions and mood disorder in AD are associated with the chronicity ischemia of cerebral heteroplasia cortex leading to neural conduction disorders. Key words: Alzheimer disease; Cerebral heteroplasia cortex; Blood floor

Morphological and functional alterations in adult boar epididymis: Effects of prenatal and postnatal administration of flutamide

BackgroundThe dynamic cross-talk between epididymal cells is hormonally regulated and, in part, through direct cell-to-cell interactions. To date, no information is available regarding possible impact of anti-androgens on the proteins involved in the gap junctional communication within the boar epididymis. Thus, a question arised whether prenatal or postnatal exposure to an anti-androgen flutamide alters the expression of gap junction protein - connexin43 (Cx43) and androgen receptor (AR) expression in the caput, corpus and cauda epididymis and leads to delayed effects on morphology and function of adult pig epididymis.MethodsFirst two experimental groups received flutamide prenatally on gestational days 20-28 and 80-88 (GD20 and GD80) and further two groups were exposed to flutamide postanatally on days 2-10 and 90-98 after birth (PD2 and PD90). Epididymides were collected from adult boars. Routine histology was performed using hematoxylin-eosin staining. The expression of Cx43 and AR were analyzed using immunohistochemistry and Western blotting. Both analyses were supported by quantitative approaches to demonstrate the variations of the expression levels following the treatment. Apoptotic cells were identified using TUNEL assay.ResultsHistological examination revealed differences in epididymal morphology of flutamide-exposed boars when compared to controls. Scarce spermatic content were seen within the corpus and cauda lumina of GD20, PD2 and PD90 groups. Concomitantly, frequency of epididymal cell apoptosis was significantly higher (p < 0.05) after exposure to flutamide at GD20. Moreover, in GD20, PD2, and PD90 groups, significantly lower AR expression (p < 0.05) was found in the principal and basal cells of the corpus and cauda regions, while in the stromal cells AR expression was significantly reduced (p < 0.05) along the epididymal duct. Concomitantly, a decrease in Cx43 expression (p < 0.05) was noticed in the stromal cells of the cauda region of GD20 and PD2 groups. This indicates high sensitivity of the stromal cells to androgen withdrawal.ConclusionsThe region-specific alterations in the epididymis morphology and scarce spermatic content within the lumina of the corpus and cauda indicate that flutamide can induce delayed effects on the epididymal function of the adult boar by decrease in AR protein levels that results in altered androgen signaling. This may cause disturbances in androgen-dependent processes including Cx43 (de)regulation, however, we can not exclude the possibility that in response to flutamide decreased Cx43 expression may represent one mechanism responsible for functional disturbance of the boar epididymis.

Hypothalamic Dynamics of CD26 Protein in Obese and Fasted Rats

Background : Impaired control of brain functions by CD26 alterations and sensing of unbalanced metabolism could be related in obese and fasting rats. This study aims to search the hypothalamic regions targeted by the alterations of CD26 and cellular activity (Fos) in monosodium glutamate obese (MSG) and food deprived (FD) rats. Methods : The patterns of distribution of immunoreactivity (ir) of CD26 and Fos were quantified in the hypothalamus. Results : Compared to control, the CD26-ir increased in the supraoptic and retrochiasmatic nuclei of MSG. CD26-ir and Fos-ir concomitantly decreased in the dorsomedial and retrochiasmatic nuclei of MSG-FD, the paraventricular nucleus of MSG and MSG-FD and in the supraoptic nucleus of FD and MSG-FD, while they exhibited opposite changes in the retrochiasmatic nucleus of FD and MSG, the arcuate and periventricular nuclei of FD, MSG and MSG-FD, the paraventricular and dorsomedial nuclei of FD and the supraoptic nucleus of MSG. Conclusions : The data provide clear evidences for regional specific alterations of CD26 together with altered cellular activity in the hypothalamus of MSG and FD animals and demonstrate that regulation of CD26 is a hallmark of hypothalamic exposure to metabolic challenges. J Endocrinol Metab. 2011;1(2):79-86 doi: https://doi.org/10.4021/jem24w

High levels of voluntary alcohol intake induces region-specific alterations in the expression of GDNF, an endogenous regulator of alcohol consumption

High levels of voluntary alcohol intake induces region-specific alterations in the expression of GDNF, an endogenous regulator of alcohol consumption

Volumetric Correlates of Spatiotemporal Working and Recognition Memory Impairment in Aged Rhesus Monkeys

Spatiotemporal and recognition memory are affected by aging in humans and macaque monkeys. To investigate whether these deficits are coupled with atrophy of memory-related brain regions, T(1)-weighted magnetic resonance images were acquired and volumes of the cerebrum, ventricles, prefrontal cortex (PFC), calcarine cortex, hippocampus, and striatum were quantified in young and aged rhesus monkeys. Subjects were tested on a spatiotemporal memory procedure (delayed response [DR]) that requires the integrity of the PFC and a medial temporal lobe-dependent recognition memory task (delayed nonmatching to sample [DNMS]). Region of interest analyses revealed that age inversely correlated with striatal, dorsolateral prefrontal cortex (dlPFC), and anterior cingulate cortex volumes. Hippocampal volume predicted acquisition of the DR task. Striatal volume correlated with DNMS acquisition, whereas total prefrontal gray matter, prefrontal white matter, and dlPFC volumes each predicted DNMS accuracy. A regional covariance analysis revealed that age-related volumetric changes could be captured in a distributed network that was coupled with declining performance across delays on the DNMS task. This volumetric analysis adds to growing evidence that cognitive aging in primates arises from region-specific morphometric alterations distributed across multiple memory-related brain systems, including subdivisions of the PFC.

Caloric Restriction Experience Reprograms Stress and Orexigenic Pathways and Promotes Binge Eating

Long-term weight management by dieting has a high failure rate. Pharmacological targets have focused on appetite reduction, although less is understood as to the potential contributions of the stress state during dieting in long-term behavioral modification. In a mouse model of moderate caloric restriction in which a 10-15% weight loss similar to human dieting is produced, we examined physiological and behavioral stress measures. After 3 weeks of restriction, mice showed significant increases in immobile time in a tail suspension test and stress-induced corticosterone levels. Increased stress was associated with brain region-specific alterations of corticotropin-releasing factor expression and promoter methylation, changes that were not normalized with refeeding. Similar outcomes were produced by high-fat diet withdrawal, an additional component of human dieting. In examination of long-term behavioral consequences, previously restricted mice showed a significant increase in binge eating of a palatable high-fat food during stress exposure. Orexigenic hormones, melanin-concentrating hormone (MCH) and orexin, were significantly elevated in response to the high-fat diet only in previously restricted mice. Furthermore, administration of the MCH receptor-1 antagonist GSK-856464 [4-(4-ethyl-5-methylsulfanyl-1,2,4-triazol-3-yl)pyridine] significantly reduced total caloric intake in these mice during high-fat access. These results reveal reprogramming of key central pathways involved in regulating stress responsivity and orexigenic drives by moderate caloric restriction experience. In humans, such changes would be expected to reduce treatment success by promoting behaviors resulting in weight regain, and suggest that management of stress during dieting may be beneficial in long-term maintenance.

An integrative assessment of brain and body function ‘at rest’ in panic disorder: A combined quantitative EEG/autonomic function study

We conducted a quantitative electroencephalographic (QEEG) and autonomic assessment of panic disorder (PD). The study samples comprised 52 individuals meeting DSM-IV criteria for PD (with or without agoraphobia) and 104 age-, gender-, and handedness-matched controls. EEG data were acquired from 16 scalp sites during resting eyes-open (REO) and eyes-closed (REC) conditions, and spectral power was assessed within 4 frequency bands: theta, alpha-1, alpha-2, and beta. The main findings were an overall reduction of spectral power in PD, compared to controls (Group main effect, p = .011), which was most apparent during REC (Group ∗ Condition interaction, p = .014), and within the alpha-1 frequency band (8–11 Hz; Group ∗ Band interaction, p = .014). Alpha-1 desynchronization occurs in response to increases in non-specific information processing, and aspects of attention such as alertness. Other findings were region-specific alterations of spectral power at frontal and temporal scalp sites, including a frontal alpha-1 asymmetry (R < L power) during REC in patients, but not controls. Findings for concomitantly-recorded autonomic measures included elevated heart rate, lower heart rate variability, and reduced rate of decrement of skin conductance level in patients, compared to controls. Finally, analyses examining the within-subjects relationship of central and peripheral function measures showed a differential pattern in patients and controls. Possible causes of these disturbances of brain and body function ‘at rest’, such as patients' ongoing automatic and strategic engagement with multiple disorder-related threat cues, including somatic variability and the testing environment, are discussed.

Differential region‐specific regulation of α4β2* nAChRs by self‐administered and non‐contingent nicotine in C57BL/6J mice

Neuronal nAChR upregulation is the hallmark of chronic nicotine exposure. Neuroplasticity to abused drugs, however, depends on whether their administration is forced by the experimenter or is under the control of the experimental animal. Neuroadaptation to chronic nicotine self-administration was examined with a yoked-control paradigm, using nose-poking as the operating procedure. Freely moving C57BL/6J mice that responded for 0.03 mg/kg/infusion of intravenous nicotine under a continuous schedule of reinforcement (FR-1), had control over the rate and amount of drug intake that a yoked littermate passively received (n = 11). The impact of response dependency on neurobiological changes in nicotinic and dopaminergic systems was subsequently assessed using quantitative autoradiography. Cytisine-sensitive [(125)I]epibatidine binding, [³H]SCH23390, [³H]raclopride and [³H]mazindol were used to label nAChRs with α4β2* subtype properties, D1 and D2 dopaminergic receptors, and dopamine transporters, respectively. During a period of 12 days, self-administration was reliably initiated and maintained in animals receiving response-contingent nicotine. Region specific changes in the density of α4β2* nAChRs were found to be dependent on the contingency of nicotine treatment. Higher levels of α4β2* receptor binding were observed in the dorsal lateral geniculate nucleus and the ventral tegmental area of self-administering mice, compared to non-contingent animals. Moreover, response-independent increases in D2 binding were observed following chronic nicotine administration. No change in D1 and DAT binding was observed among groups. These findings indicate regional specific alterations in the regulation of the nicotinic cholinergic system following contingent and non-contingent nicotine exposure, and underline the importance of response dependency on the development of nicotine addiction.

Sex‐dimorphic changes in neuroactive steroid levels after chronic experimental autoimmune encephalomyelitis

Our previous observations have shown that neuroactive steroid levels in the brain are affected by acute experimental autoimmune encephalomyelitis (EAE) with sex and regional specificity (Giatti et al. 2010). To better understand the effect of EAE on neuroactive steroids, we have here assessed the levels of pregnenolone, progesterone and its derivatives (i.e. dihydroprogesterone, tetrahydroprogesterone and isopregnanolone), testosterone and its derivatives (dihydrotestosterone and 5alpha-androstane-3alpha, 17beta-diol) in different CNS regions of male and female rats affected by chronic EAE. Data obtained by liquid chromatography tandem mass spectrometry revealed that chronic EAE results in sex and regional specific alterations in the levels of neuroactive steroids in the brain, which are in many cases different to those produced by acute EAE. The specific changes in neuroactive steroid levels after chronic EAE may be of relevance to design new possible therapeutic strategies for the disease.

Region and diagnosis-specific changes in synaptic proteins in schizophrenia and bipolar I disorder

Aberrant regulation of synaptic function is thought to play a role in the aetiology of psychiatric disorders, including schizophrenia and bipolar disorder. Normal neurotransmitter release is dependent on a complex group of presynaptic proteins that regulate synaptic vesicle docking, membrane fusion and fission, including synaptophysin, syntaxin, synaptosomal-associated protein-25 (SNAP-25), vesicle-associated membrane protein (VAMP), α-synuclein and dynamin I. In addition, structural and signalling proteins such as neural cell adhesion molecule (NCAM) maintain the integrity of the synapse. We have assessed the levels of these important synaptic proteins using Western blots, in three cortical regions (BA10, 40 and 46) obtained post-mortem from subjects with bipolar 1 disorder, schizophrenia or no history of a psychiatric disorder. In bipolar 1 disorder cortex (parietal; BA40), we found a significant increase in the expression of SNAP-25, and a significant reduction in α-synuclein compared with controls. These changes in presynaptic protein expression are proposed to inhibit synaptic function in bipolar 1 disorder. In schizophrenia, a significant reduction in the ratio of the two major membrane-bound forms of NCAM (180 and 140) was observed in BA10. The distinct functions of these two NCAM forms suggest that changes in the comparative levels of these proteins could lead to a destabilisation of synaptic signalling. Our data support the notion that there are complex and region-specific alterations in presynaptic proteins that may lead to alterations in synaptic activity in both schizophrenia and bipolar disorder.

Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome

Longitudinal neuroimaging investigation of fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism, provides an opportunity to study the influence of a specific genetic factor on neurodevelopment in the living human brain. We examined voxel-wise gray and white matter volumes (GMV, WMV) over a 2-year period in 1- to 3-year-old boys with FXS (n = 41) and compared these findings to age- and developmentally matched controls (n = 28). We found enlarged GMV in the caudate, thalamus, and fusiform gyri and reduced GMV in the cerebellar vermis in FXS at both timepoints, suggesting early, possibly prenatal, genetically mediated alterations in neurodevelopment. In contrast, regions in which initial GMV was similar, followed by an altered growth trajectory leading to increased size in FXS, such as the orbital gyri, basal forebrain, and thalamus, suggests delayed or otherwise disrupted synaptic pruning occurring postnatally. WMV of striatal-prefrontal regions was greater in FXS compared with controls, and group differences became more exaggerated over time, indicating the possibility that such WM abnormalities are the result of primary FMRP-deficiency-related axonal pathology, as opposed to secondary connectional dysregulation between morphologically atypical brain structures. Our results indicate that structural abnormalities of different brain regions in FXS evolve differently over time reflecting time-dependent effects of FMRP deficiency and provide insight into their neuropathologic underpinnings. The creation of an early and accurate human brain phenotype for FXS in humans will significantly improve our capability to detect whether new disease-specific treatments can "rescue" the FXS phenotype in affected individuals.

Effects of Optical Defocus on Refractive Development in Monkeys: Evidence for Local, Regionally Selective Mechanisms

To characterize the influence of optical defocus on ocular shape and the pattern of peripheral refraction in infant rhesus monkeys. Starting at 3 weeks of age, eight infant monkeys were reared wearing -3 diopter (D) spectacle lenses over one eye that produced relative hyperopic defocus in the nasal field (NF) but allowed unrestricted vision in the temporal field (NF group). Six infants were reared with monocular -3 D lenses that produced relative hyperopic defocus across the entire field of view. Control data were obtained from 11 normal monkeys. Refractive development was assessed by streak retinoscopy performed along the pupillary axis and at eccentricities of 15 degrees, 30 degrees, and 45 degrees along the vertical and horizontal meridians. Central axial dimensions and eye shape were assessed with magnetic resonance imaging. In response to full-field hyperopic defocus, the eye developed relative central axial myopia, became less oblate, and exhibited relative peripheral hyperopia in both the nasal and the temporal hemifields. Conversely, nasal-field hyperopic defocus produced relative myopia that was largely restricted to the nasal hemifield; these alterations in the patterns of peripheral refraction in the NF monkeys were associated with local, region-specific alterations in vitreous chamber depth in the treated hemiretina. Optically imposed defocus can alter the shape and pattern of peripheral refraction in infant primates. Like those of form deprivation, the effects of optical defocus in primates are dominated by mechanisms that integrate visual signals in a spatially restricted manner and exert their influence in a regionally selective manner.

Region-specific genetic alterations in the aging hippocampus: implications for cognitive aging.

Aging is associated with cognitive decline in both humans and animals and of all brain regions, the hippocampus appears to be particularly vulnerable to senescence. Age-related spatial learning deficits result from alterations in hippocampal connectivity and plasticity. These changes are differentially expressed in each of the hippocampal fields known as cornu ammonis 1 (CA1), cornu ammonis 3 (CA3), and the dentate gyrus. Each sub-region displays varying degrees of susceptibility to aging. For example, the CA1 region is particularly susceptible in Alzheimer's disease while the CA3 region shows vulnerability to stress and glucocorticoids. Further, in animals, aging is the main factor associated with the decline in adult neurogenesis in the dentate gyrus. This review discusses the relationship between region-specific hippocampal connectivity, morphology, and gene expression alterations and the cognitive deficits associated with senescence. In particular, data are reviewed that illustrate how the molecular changes observed in the CA1, CA3, and dentate regions are associated with age-related learning deficits. This topic is of importance because increased understanding of how gene expression patterns reflect individual differences in cognitive performance is critical to the process of identifying new and clinically useful biomarkers for cognitive aging.