Biomedical subjects

Y L Hurd

Publications and source records attributed to Y L Hurd.

At least 37 records · Page 2Linked to original sources

PubMed2000

Estrogen receptor beta (ERbeta) messenger ribonucleic acid (mRNA) expression within the human forebrain: distinct distribution pattern to ERalpha mRNA.

Estrogen has been shown to influence several brain functions as well as the expression of neuropsychiatric diseases. To date, two estrogen receptor (ER) subtypes have been identified, ERalpha and ERbeta. ERalpha messenger ribonucleic acid (mRNA) distribution in the human forebrain was recently characterized, and the highest expression was found in restricted areas of the amygdala and hypothalamus. However, no information exists with regard to ERbeta mRNA distribution in the human brain. To this end, the anatomical distribution pattern of ERbeta mRNA expression in the human forebrain was investigated in the present study. Overall, the ERbeta mRNA hybridization signal was relatively low, but the most abundant ERbeta mRNA areas were the hippocampal formation (primarily the subiculum), claustrum, and cerebral cortex; expression was also present in the subthalamic nucleus and thalamus (ventral lateral nucleus). In contrast to ERalpha (studied on adjacent brain sections), ERbeta mRNA expression was low in the hypothalamus and amygdala. Based on the revealed anatomical distribution of the human ERbeta gene expression, a putative role for ERbeta in the modulation of cognition, memory, and motor functions is suggested.

Adolescent↗

PubMed1999

The flinders sensitive line rats, a genetic model of depression, show abnormal serotonin receptor mRNA expression in the brain that is reversed by 17beta-estradiol.

The possible link between estrogen and serotonin (5-HT) in depression was investigated using a genetic animal model of depression, the Flinders Sensitive Line (FSL) rats, in comparison to control Flinders Resistant Line rats. The mRNA levels of the estrogen receptor (ER) alpha and beta subtypes and the 5-HT(1A) and 5-HT(2A) receptors were analyzed in several limbic-related areas of ovariectomized FSL and FRL rats treated with 17beta-estradiol (0.15 microg/g) or vehicle. The FSL animals were shown to express significantly lower levels of the 5-HT(2A) receptor transcripts in the perirhinal cortex, piriform cortex, and medial anterodorsal amygdala and higher levels in the CA 2-3 region of the hippocampus. The only significant difference between the rat lines in ER mRNA expression was found in the medial posterodorsal amygdala, where the FSL rats showed lower ERalpha expression levels. Overall, estradiol treatment increased 5-HT(2A) and decreased 5-HT(1A) receptor mRNA levels in several of the examined regions of both lines. Thus, in many areas, estradiol was found to regulate the 5-HT receptor mRNA expression in the opposite direction to the alterations found in the FSL rats. These findings further support the implication of 5-HT receptors, in particular the 5-HT(2A) subtype, in the etiology of affective disorders. Moreover, the ability of estradiol to regulate the expression of the 5-HT(1A) and 5-HT(2A) receptor genes might account for the reported influence of gonadal hormones in mood and depression.

Animals↗

PubMed1999

Mesolimbic gender differences in peptide CART mRNA expression: effects of cocaine.

The putative neurotransmitter peptide CART has been suggested to be involved in the actions of psychostimulants. We analyzed the CART mRNA expression in mesolimbic brain areas of male and ovariectomized 17beta-estradiol- (30 microg) and vehicle-treated female rats. A gender difference was noted in the accumbens shell during basal conditions; male rats expressed higher levels of CART mRNA than both female groups. Following binge cocaine injections (3 x 15 mg/kg), elevated levels were found in the central amygdala of male but not female rats. In the medial accumbens shell CART mRNA was elevated after cocaine, but only in the non-treated females. The present results support a role of mesolimbic CART in psychostimulant drug action.

Amygdala↗

PubMed1999

Structure, chromosomal localization, and brain expression of human Cx36 gene.

Rat connexin-36 (Cx36) is the first gap junction protein shown to be expressed predominantly in neuronal cells of the mammalian central nervous system. As a prerequisite for studies devoted to the investigation of the possible role of this connexin in human neurological diseases, we report the cloning and sequencing of the human Cx36 gene, its chromosomal localization, and its pattern of expression in the human brain analyzed by radioactive in situ hybridization. The determination of the human gene sequence revealed that the coding sequence of Cx36 is highly conserved (98% identity at the protein level with the mouse and rat Cx36 and 80% with the ortholog perch and skate Cx35), and that the gene structure is that typical of the Cx35/36 subgroup observed in the other species (presence of a single intron located within the coding region, 71 bp after the translation initiation site). The distribution of Cx36 in several regions of the human central nervous system is similar to that previously observed in rat brain. The most intense signal among the cerebral areas examined by in situ hybridization was observed in the inferior olivary complex, both in principal and accessory nuclei. A moderate labeling was also observed in several myelencephalic nuclei, in specific cells of the the cerebellar cortex, in a relatively large subpopulation of cells in the cerebral cortex, in the hilus of the dentate gyrus, and in the strata radiatum and oriens of hippocampal subfields. Moreover, labeled cells were revealed in all the lamina of the spinal cord gray matter. The chromosomal localization of the human Cx36 gene was determined by fluorescence in situ hybridization. The results allowed assignment of the gene to band 15q14, thus making it a possible candidate gene for a form of familial epilepsy previously linked to the same chromosomal band. The knowledge of the human Cx36 gene sequence, of its chromosomal localization, and of its pattern of expression opens new avenues for the analysis of its possible involvement in human genetic and acquired neuropathology.

Adolescent↗

PubMed1999

Preprotachykinin-A mRNA expression in the human and monkey brain: An in situ hybridization study.

The mRNA expression for preprotachykinin-A (PPT-A) was studied throughout the human and cynomolgus monkey brain to assess the neuroanatomical expression pattern of the PPT-A gene in primates. In situ hybridization showed that the PPT-A mRNA is expressed highly in specific regions of the postmortem human brain, including the striatum, islands of Calleja, hypothalamus (posterior, premammillary, medial mammillary, and ventromedial nuclei), superior and inferior colliculi, periaqueductal gray, and oculomotor nuclear complex. PPT-A mRNA-expressing neurons also were present in the paranigralis (ventral tegmental area) and were scattered in the bed nucleus stria terminalis throughout the sublenticular substantia innominata region, including the diagonal band of Broca and the nucleus basalis of Meynert. In the hippocampus, high PPT-A mRNA expression was localized predominantly to the polymorphic layer of the dentate gyrus; no labeled cells were present in the granular layer. Positively labeled cells also were found scattered in the CA regions as well as in the amygdaloid complex. Neocortical expression of PPT-A mRNA was localized mainly to the deep laminae (layers V/VI), except for the striate cortex (labeling was seen also in superficial layers). The subiculum, thalamus, globus pallidus, ventral pallidum, substantia nigra pars compacta, red nucleus, pontine nuclei, and cerebellum were characterized by very weak to undetectable expression of PPT-A mRNA. An expression pattern was evident in the monkey forebrain similar to that observed in the human, except for the absence of PPT mRNA-expressing cells in the medial mammillary nucleus despite intense expression in supramammillary, lateral mammillary, and premammillary nuclei. Overall, more similarities than differences are apparent between primate species in the expression pattern of the PPT-A gene. J. Comp. Neurol. 411;56-72, 1999.

Adult↗

PubMed1999

The role of dopamine, dynorphin, and CART systems in the ventral striatum and amygdala in cocaine abuse.

Disturbance of the mesolimbic dopamine system has long been hypothesized for the underlying neurobiology of cocaine addiction. Recently, increased attention has been directed towards the opioid neuropeptide system, in particular dynorphin; inasmuch as opioid peptide-containing neurons are regulated by dopamine, these peptides have potent effects on mood and reward, and cocaine consistently modulates dynorphin activity. Our experiments have been directed towards characterizing the specific alterations of dopamine and dynorphin systems during different stages following cocaine administration, as well as assessing the contribution of nucleus accumbens and amygdala dopamine levels to cocaine-intake behavior. We have used the techniques of in vivo microdialysis to measure and manipulate extracellular concentrations of dopamine in animals that self-administer cocaine, and in situ hybridization to study mRNA expression levels of prodynorphin and dopamine receptors. It is clear from these studies that different stages of the cocaine use cycle are characterized by distinct patterns of prodynorphin and dopamine D1 mRNA expression levels. Moreover, cocaine-intake behavior is sensitive to very specific concentrations of dopamine in the nucleus accumbens as well as in the amygdala. Recently, the CART (cocaine and amphetamine-regulated transcript) peptide was proposed as a novel target for the actions of psychostimulant drugs. We have noted differences between male and female rats in the mesolimbic mRNA expression of CART that might be relevant for gender differences apparent in drug abuse.

Amphetamine↗

PubMed1999

Reduced neuropeptide Y mRNA expression in the prefrontal cortex of subjects with bipolar disorder.

In the present study, we compared neuropeptide Y mRNA expression levels in the prefrontal cortex (Brodmann area 9 and 46) of subjects diagnosed with major depression, bipolar disorder and schizophrenia with those in normal controls without a psychiatric history. No correlation was found regarding neuropeptide Y mRNA expression and postmortem interval, age, gender, hemisphere side, suicide as cause of death, or the history of use of substances such as alcohol, marihuana and cocaine/amphetamine. The only significant alteration found was related to the clinical diagnosis; neuropeptide Y mRNA expression was reduced in the group of bipolar subjects as compared to the controls. Overall, the present results confirm an involvement of neuropeptide Y in affective disorders, and show for the first time a specific association between NPY and bipolar disorder.

Adult↗

PubMed1999

Alterations in neuropeptide Y levels and Y1 binding sites in the Flinders Sensitive Line rats, a genetic animal model of depression.

Previously, we observed specific alterations of neuropeptide Y (NPY) and Y1 receptor mRNA expression in discrete regions of the Flinders Sensitive Line rats (FSL), an animal model of depression. In order to clarify the correlation between mRNA expression and protein content, radioimmunoassay and receptor autoradiography were currently performed. In the FSL rats, NPY-like immunoreactivity (NPY-LI) was decreased in the hippocampal CA region, while Y1 binding sites were increased; NPY-LI was increased in the arcuate nucleus. Fluoxetine treatment elevated NPY-LI in the arcuate and anterior cingulate cortex and increased Y1 binding sites in the medial amygdala and occipital cortex in both strains. No differences were found regarding the Y2 binding sites. The results demonstrate a good correlation between NPY peptide and mRNA expression, and sustain the possible involvement of NPY and Y1 receptors in depression.

Amygdala↗

PubMed1999

A heroin-, but not a cocaine-expecting, self-administration state preferentially alters endogenous brain peptides.

The purpose of the current study was to assess neuropeptidergic alterations during a phase of the drug addiction cycle associated with drug craving as compared to a time period when the drug had been recently self-administered. Male Wistar rats were allowed to self-administer cocaine, heroin or saline for 6 h for 5 consecutive days. Immediately following the last self-administration session ('acute drug on board' state), and just before the next scheduled session ('drug expecting' state), the animals were decapitated and the levels of dynorphin A and B, [Met5]- and [Leu5]-enkephalin and substance P were measured in different brain areas. During the 'acute drug on board' state, peptide levels in animals that self-administered heroin or cocaine were not significantly changed. In contrast, during the 'drug expecting' state, heroin-treated animals had increased levels of dynorphin A, dynorphin B and [Met5]-enkephalin in the caudal striatum as compared to the cocaine- and saline-treated animals, and the level of [Leu5]-enkephalin was increased as compared to the cocaine-treated group. In the septum, an increase of [Met5]-enkephalin and substance P was observed in the animals expecting heroin as compared to the saline- and/or cocaine-treated animals. In the caudal striatum, substance P levels were elevated in the heroin- and cocaine-expecting animals. In conclusion, heroin, as compared to cocaine, appears to have a more pronounced effect on dynorphin, enkephalin and substance P levels in the caudal striatum and septum, especially during periods when self-administration of the drug is expected.

Animals↗

PubMed1999

A novel neuron-specific DNA end-binding factor in the murine brain.

To characterize the distribution of transcription factor AP-1 and YY1 DNA-binding activities in the rat brain, the labeled target oligonucleotides were loaded on brain sections and after incubation and washing, the residual signal was registered by autoradiography. The binding was predominantly associated with neurons and was regionally specific with highest levels in the cerebellum, hippocampus, and piriform cortex. The identified binding factor was not, however, sequence-specific, but apparently recognized DNA ends and was activated by long double-stranded DNA. UV cross-linking identified the molecular mass of the factor to be about 80 kDa. The factor was not found in soluble brain extracts, suggesting its association with membranes or the nuclear matrix. Despite apparent similarities with Ku protein, which targets DNA-ends, the DNA end-binding activity was present in brains of Ku86- and Ku70-deficient mice. Since DNA end-binding factors are generally involved in DNA repair, the same function may be suggested for the novel factor identified in the present study.

Animals↗

PubMed1998

Perinatal cocaine decreases the expression of prodynorphin mRNA in nucleus accumbens shell in the adult rat.

Preprodynorphin mRNA expression in the striatal-olfactory tubercle complex was studied in adult rats exposed to cocaine (50 mg/kg) during postnatal days (PnD) 11-20. While multiple regions of the striatum and olfactory tubercle were examined, alterations were only found in the nucleus accumbens. A 50% and 20% reduction in expression within the shell region was observed at 1.2 and 1.7 mm rostral to Bregma respectively. While the core regions at these levels were unaffected, the rostral accumbens showed a trend toward an increase in expression in the cocaine-treated rats. These findings, in combination with other behavioral and neurochemical data collected on similarly treated rats, suggest that perinatal cocaine produces a long-term dampening of function in a specific population of neurons within the mesolimbic system

Animals↗

PubMed1998

Alterations in neuropeptide Y and Y1 receptor mRNA expression in brains from an animal model of depression: region specific adaptation after fluoxetine treatment.

To investigate the possible link between neuropeptide Y (NPY) and depression, we analyzed NPY and its receptors in different limbic-related regions in the Flinder sensitive line (FSL), a genetic animal model of depression. In situ hybridization histochemistry was used to measure mRNA expression levels of NPY and NPY receptors, Y1 and Y2, in the FSL as compared to the control Flinder resistant Line rats (FRL). In the FSL rats, NPY mRNA expression levels were significantly decreased in the nucleus accumbens and CA regions, but increased in the arcuate nucleus and anterior cingulate cortex. Y1 receptor mRNA expression was decreased in different cortical regions (retrosplenial, anterior cingulate, and occipital) and in the hippocampal dentate gyrus. Y2 mRNA expression levels did not differ between FSL and FRL animals. The effect of the antidepressant drug fluoxetine (a serotonin reuptake inhibitor) in the two rat strains was also studied. There was an increase of the NPY mRNA hybridization signal in the arcuate nucleus of both strains following the antidepressant treatment (10 micromol/kg; daily for 14 days). However, in other brain regions, fluoxetine administration caused a differential effect on the induction of NPY-related genes in the two rat strains: in the CA region and dentate gyrus NPY mRNA expression was increased in the FSL, but decreased in the FRL. In contrast, Y1 mRNA levels tended to be decreased by fluoxetine in the nucleus accumbens of the FSL rats, but increased in the FRL. These findings suggest an involvement of the Y1, but not the Y2, receptor subtype in depressive disorder. Overall, the results appear to sustain the importance of the FSL rats as an animal model of depression in view of the impairment of NPY genes and the ability of fluoxetine treatment to normalize NPY-related gene expression selectively in this strain.

Animals↗

PubMed1998

Autoantigen Ku in the brain. Developmentally regulated expression and subcellular localization.

A double-stranded DNA end-binding factor with high levels of expression in brain and testis of adult mice was identified as the Ku protein, earlier described as an autoantigen in connective tissue diseases and found to be essential for recombination of the immunoglobulin genes and DNA repair. High Ku levels were found in the cerebellum and pituitary gland, lower levels in the hippocampus, hypothalamus and white matter structures. Ku levels were much higher in embryonic rat brain than in the adult brain, suggesting a role of the Ku protein in brain development. In embryonic rat brain, Ku was associated with cell nuclei, but was predominantly located in the cytosol in the adult rat cerebellum and hippocampus. The abundant expression of Ku in the brain suggests the involvement of Ku autoantibodies in the pathogenesis of neuropsychiatric complications in connective tissue diseases.

Animals↗

PubMed1998

Acute 17 beta-estradiol treatment down-regulates serotonin 5HT1A receptor mRNA expression in the limbic system of female rats.

In situ hybridization histochemistry was used to investigate acute estrogen effects on serotonin 5HT1A receptor mRNA levels in limbic-related brain areas in the female ovariectomized rat. Acute administration of 17 beta-estradiol (10 micrograms) decreased 5HT1A receptor mRNA expression levels within the medial amygdala (after 2 and 24 h), piriform cortex (after 2 and 24 h), and perirhinal cortex (after 24 h). No changes in 5HT1A mRNA levels were observed in hippocampus or retrosplenial cortex. The findings suggest specific regional effects of estrogen on 5HT functions mediated through regulation of the 5HT1A gene.

Affect↗

PubMed1998

D3 dopamine receptor mRNA is widely expressed in the human brain.

Considerable attention has been given to the association of the D3 dopamine receptor subtype and limbic function based on the abundant localization of D3 receptor sites and mRNA expression in the islands of Calleja and nucleus accumbens in experimental animals. Though most human anatomical studies have focused on the role of D3 receptors in limited brain structures, detailed information about the overall anatomical organization of the D3 receptor in the human brain is still, however, not available. In the current study, we examined the anatomical distribution of D3 receptor mRNA expression at different levels of the human brain in whole hemisphere horizontal cryosections using in situ hybridization. This approach made it possible to establish for the first time the wide and heterogenous expression of the D3 receptor gene throughout the human brain. As expected, the most abundant D3 mRNA expression levels were found in the islands of Calleja and discrete cell cluster populations within the ventral striatum/nucleus accumbens region. High levels were also evident within the dentate gyrus and striate cortex. Low to moderate D3 mRNA expression levels were apparent in most brain areas including all other cortical regions (highest in the anterior cingulate/subcallosal gyrus), caudate nucleus, putamen, anterior and medial thalamic nucleus, mammillary body, amygdala, hippocampal CA region, lateral geniculate body, substantia nigra pars compacta, locus coeruleus, and raphe nuclei. While the current anatomical map of D3 receptor mRNA expression in the human brain does confirm previous reports that D3 receptors may play important roles in limbic-related functions such as emotion and cognition, the findings also suggest other non-limbic functions for D3 mRNA-expressing cell populations such as processing of motor and sensory information.

Brain Chemistry↗

PubMed1998

Differential distribution and regulation of estrogen receptor-alpha and -beta mRNA within the female rat brain.

In the present study, estrogen receptor (ER)alpha and ER beta genes were found to be differentially expressed in discrete subregions of the rat amygdaloid complex. The amygdala nuclei showing predominant ER alpha mRNA expression included the posterolateral cortical nucleus, amygdala hippocampal area, and lateral dorsolateral nucleus, whereas the amygdala areas with predominant ER beta mRNA expression were the medial anterodorsal and central nuclei. Both ER alpha and ER beta mRNAs were highly expressed in the medial posterodorsal nucleus. In addition to the discrete anatomical expression patterns, there appeared to be a differential regulation by estradiol of the ER alpha and ER beta mRNAs. Two weeks of estradiol (170 microgram total) treatment decreased ER alpha mRNA expression levels in the arcuate, ventromedial hypothalamus, and posterolateral cortical amygdala nucleus, but increased ER beta mRNA in the arcuate. In the medial amygdala nuclei, only ER beta mRNA levels were altered (reduced) by estradiol treatment. These results suggest that estrogen can modulate behaviors and functions mediated by the amygdala and hypothalamus via differentially regulated ER subtypes.

Animals↗

PubMed1998

Specific reductions of striatal prodynorphin and D1 dopamine receptor messenger RNAs during cocaine abstinence.

It is well established that the opioid neuropeptide and dopamine systems are altered following the use of cocaine. However very little information is available about their possible involvement during cocaine abstinence. In the present study, the mRNA expression of the dopamine receptors, D1 and D2, and the opioid peptides, prodynorphin and proenkephalin, were analyzed in the rat striatum using in situ hybridization histochemistry. Saline or cocaine (30 mg/kg, i.p.) were administered to rats once daily for 1 or 10 days. To examine cocaine abstinence, animals were treated for 10 days as described followed by a 10-day drug free period. Acute and intermittent cocaine administration elevated the prodynorphin mRNA expression in the dorsal striatum, consistent with previous reports, while the abstinent phase resulted in a significant reduction of prodynorphin mRNA levels in the ventrorostral striatum. The D1-receptor mRNA was decreased in the caudorostral striatum during cocaine withdrawal, a finding opposite to the increase observed following a single injection of the drug. Proenkephalin and the D2-receptor mRNAs were not altered during cocaine abstinence, though proenkephalin was elevated following acute but not repeated cocaine administration. These results show long-term suppression on prodynorphin and D1-receptor systems in specific striatal populations localized mainly in rostral areas during withdrawal from cocaine.

Animals↗

PubMed1998

Regional distribution of neuropeptide Y Y2 receptor messenger RNA in the human post mortem brain.

The neuropeptide Y Y2 receptor is one of six receptor subtypes mediating the multiform physiological actions of neuropeptide Y. The Y2 receptor has been demonstrated to be the most predominant receptor subtype in the human brain and appears to be involved in many neuropeptide Y actions, such as the regulation of locomotor activity, cardiovascular functions, memory processing, circadian rhythms and release of other neurotransmitters. We have recently demonstrated the widespread and abundant distribution of neuropeptide Y Y1 receptor messenger RNA in the human cerebral cortex (different laminar patterns within distinct cortical regions), hippocampal dentate gyrus and striatum. To assess a possible differential distribution of Y1 and Y2 receptor messenger RNAs, the regional expression of neuropeptide Y Y2 messenger RNA-containing cells in the human brain was analysed, in particular within the cerebral cortex and striatum. In situ hybridization experiments revealed the localization of the Y2 messenger RNA signal throughout all cortical regions, with the highest intensity per cell apparent in lamina IV, with the exception of the striate cortex, which showed an intense labelling primarily in layer VI. The striatum expressed low to undetectable levels of the Y2 receptor messenger RNA. The dentate gyrus and the CA2 region presented the highest hybridization signals, while a very weak Y2 messenger RNA expression was found in the CA1 region and subiculum. Positive Y2 messenger RNA hybridization signals were also detected in the lateral geniculate nucleus, amygdala, substantia nigra, hypothalamus, cerebellum and choroid plexus. These results demonstrate the widespread distribution of neuropeptide Y Y2 receptor messenger RNA in the human brain, with a pattern of expression distinct from the Y1 subtype, suggesting that these two receptor subtypes may mediate different neuropeptide Y functions in the human brain, mainly through actions on different neuronal systems.

Adult↗