Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studie... more Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.
Previous investigations have combined transcriptional and genetic analyses in human cell lines, b... more Previous investigations have combined transcriptional and genetic analyses in human cell lines, but few have applied these techniques to human neural tissue. To gain a global molecular perspective on the role of the human genome in cortical development, function and ageing, we explore the temporal dynamics and genetic control of transcription in human prefrontal cortex in an extensive series of
Numerous genetic linkage and association reports have implicated the Disrupted-in-Schizophrenia (... more Numerous genetic linkage and association reports have implicated the Disrupted-in-Schizophrenia (DISC1) gene in psychiatric illness. The Scottish family translocation, predicted to encode a C-terminus-truncated protein, suggests involvement of short isoforms in the pathophysiology of mental disorders. We recently reported complex alternative splicing patterns for the DISC1 gene and found that short isoforms are overexpressed in the brains of patients with schizophrenia and in carriers of risk-associated alleles. Investigation into the protein-protein interactions of alternative DISC1 isoforms may provide information about the functional consequences of overexpression of truncated forms in mental illness. Human embryonic kidney (HEK293) cells were transiently co-transfected with human epitope-tagged DISC1 variants and epitope-tagged NDEL1, FEZ1, GSK3β and PDE4B constructs. Co-immunoprecipitation assays demonstrated that all truncated DISC1 variants formed complexes with full-length D...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
Rats with neonatal excitotoxic damage of the ventral hippocampus display in adulthood a variety o... more Rats with neonatal excitotoxic damage of the ventral hippocampus display in adulthood a variety of abnormalities reminiscent of schizophrenia and are used as an animal model of this disorder. In the present study, we hypothesized that transient inactivation of ventral hippocampal activity during a critical developmental period may be sufficient to disrupt normal maturation of relevant brain systems and produce similar lasting behavioral changes. We infused tetrodotoxin (TTX) or artificial CSF into the ventral hippocampus on postnatal day 7 (P7) and assessed behavioral changes in response to stress, amphetamine, and (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate in juvenile (P35) and young adult (P56) rats. In adulthood, rats infused neonatally with TTX displayed motor hyperactivity after pharmacological stimulation and after stress compared with sham controls. Analogous TTX infusions in adult animals did not alter these behaviors later in life. These data...
Proceedings of the National Academy of Sciences of the United States of America, Jan 25, 2006
Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated... more Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5' upstream region of the gene for their effects on mRNA abundance of NRG1 types I-IV in human postmortem hippocampus. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain/loss of putative binding sites for three transcription ...
Rats with excitotoxic neonatal ventral hippocampal lesions (NVHL) manifest in early adulthood a v... more Rats with excitotoxic neonatal ventral hippocampal lesions (NVHL) manifest in early adulthood a variety of behavioral and neurochemical abnormalities mimicking those seen in patients with schizophrenia. Some of these aberrations implicate malfunction of the midbrain dopamine systems. We studied NVHL effects on dopamine release in the rat frontal cortex, nucleus accumbens, and striatum during acute stress caused by inescapable continuous footshock (0.45 mA). Serum total corticosterone and prolactin levels were used as peripheral indices of stress. As an indirect index of dopamine release, tissue 3-methoxytyramine levels attained in vivo 10 min after monoamine oxidase inhibition was assayed in rats sacrificed by instantaneous microwave fixation of the brain tissue. Nonshocked NVHL rats showed significantly less nucleus accumbens' 3-methoxytyramine accumulation than their sham counterparts. Frontal cortical 3-methoxytyramine levels rose similarly after 20-min footshock in both groups of rats, but while it normalized after 60-min footshock in the sham rats, it did not decrease in the NVHL rats. Nucleus accumbens' 3-methoxytyramine was significantly elevated after either 20-min or 60-min footshock in both groups, whereas striatal 3-methoxytyramine was significantly elevated in the NVHL rats only. Serum corticosterone showed similar elevations in the sham and NVHL rats, but the patterns differed in that there was no attenuation after 60-min footshock in the latter. The lesion did not affect serum prolactin response. These data indicate that neonatal ventral hippocampal damage enhances and prolongs certain neural and neuroendocrine responses to acute physical stressor(s), and thus may affect adaptation and enhance detrimental effects of stress.
The effects of neonatal excitotoxic ventral hippocampus (VH) lesions on dopamine release in respo... more The effects of neonatal excitotoxic ventral hippocampus (VH) lesions on dopamine release in response to repeated stress (saline injections) and to chronic haloperidol treatment were investigated in Sprague-Dawley rats infused with ibotenic acid or vehicle into the VH on day 7 of postnatal life (PD7). Beginning on PD35, lesioned and sham-operated rats were injected i.p. with saline (INJ) once daily for 3 weeks or were not treated (NO INJ). Another cohort of rats was given haloperidol (HAL, 0.4 mg/kg, i.p.) or vehicle beginning on PD35 and thereafter once daily for 3 weeks. 3-Methoxytyramine (3-MT) was measured by combined gas chromatography/mass spectrometry in the frontal cortex (FC), nucleus accumbens (NAcc), and striatum (STR) at PD56 following MAO inhibition with pargyline. At baseline (NO INJ), 3-MT was reduced in STR of lesioned rats. Repeated saline injections resulted in a further 3-MT reduction in STR, FC, and NAcc of lesioned animals, but had no effect in sham rats. Chronic HAL, compared with vehicle, suppressed locomotor activity, and increased 3-MT accumulation in the FC, NAcc, and STR in sham and lesioned rats. This increase was enhanced in the FC of lesioned rats. These data show that mild repeated stress attenuates dopamine release in FC, NAcc, and STR of lesioned rats, while chronic HAL augments it in FC of lesioned animals versus controls. We conclude that the neonatal excitotoxic lesion of VH alters the functioning of midbrain dopamine systems during environmental and pharmacological challenge.
Two of the favorite hypotheses of schizophrenia research-maldevelopment of cerebral cortex and ma... more Two of the favorite hypotheses of schizophrenia research-maldevelopment of cerebral cortex and malfunction of brain dopamine systems-have often seemed difficult to reconcile. This article reviews recent research that suggests a heuristically useful reconciliation centered on the functional neuroanatomical concept of prefrontal-temporolimbic cortical connectivity. Anatomical findings from postmortem studies and neuropsychological and neuroimaging studies of brain function in patients with schizophrenia have implicated a developmental 'dysconnection' of temporolimbic-prefrontal cortices. The possibility that such dysconnection can account for the principal phenomenology of the illness, including its delayed onset and its treatment, is suggested by neurologic disease analogies such as metachromatic leukodystrophy and by recent studies in animals with developmental cortical lesions. Studies mapping neuronal gene expression indicate that all antipsychotic drugs modulate DNA transcription in a region of the nucleus accumbens that receives converging inputs from prefrontal and temporolimbic cortices, suggesting that indirect compensation for dysfunctional communication between prefrontal and temporolimbic cortices is a therapeutic mechanism of these drugs. Treatments aimed at direct cortical compensation may be more effective.
The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of sev... more The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of several aspects of schizophrenia. This lesion produces a number of behavioural abnormalities, such as hyperlocomotion and deficits in prepulse inhibition of startle, that present themselves relatively late in development, i.e. after puberty. Some of these abnormalities, which are thought to model the positive symptoms of schizophrenia, can be normalized by chronic treatment with neuroleptics. In the present study, we examined the effects of the neonatal hippocampal lesion on social behaviour. Social withdrawal and isolation are key components of the negative symptoms of schizophrenia that have not been previously addressed in this model. Rats were lesioned on postnatal day 7 (PD7) and tested for social interaction on PD35 and PD65. They were then treated with clozapine (1.9 and 7.4 micromol/kg or 0.63 and 2.5 mg/kg) for 21 days and retested. The results show that although, as previously reported, spontaneous hyperlocomotion emerged in the lesioned rats only after puberty (PD65), social interaction deficits and behaviors that may reflect anxiety were present at both PD35 and PD65. Clozapine normalized locomotion, but did not ameliorate putative anxiety or social interaction deficits in the neonatally lesioned rats. Our results indicate that the neonatal hippocampal lesion in the rat models some aspects of both positive and negative symptoms of schizophrenia. The effects of clozapine appear inconsistent with its putative benefit for negative symptoms.
This study assessed the effects of central serotonergic depletion on exploratory activity at base... more This study assessed the effects of central serotonergic depletion on exploratory activity at baseline, as well as after administration of d-amphetamine or the anxiogenic beta-carboline FG-7142. Intraventricular 5,7-dihydroxytryptamine (5,7-DHT) induced an almost complete depletion of serotonin [5-hydroxytryptamine (5-HT)] in the medial prefrontal cortex, nucleus accumbens, medial corpus striatum, and hippocampus with no changes in norepinephrine, dopamine or dihydroxyphenylacetic acid concentrations. 5-HT-depleted rats demonstrated reduced spontaneous and d-amphetamine-augmented exploration 3-10 weeks postoperatively. An effect on FG-7142-induced inhibition of exploratory activity was not apparent. These data implicate 5-HT systems in the expression of different aspects of exploratory and amphetamine-augmented motor behaviors.
Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studie... more Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.
Previous investigations have combined transcriptional and genetic analyses in human cell lines, b... more Previous investigations have combined transcriptional and genetic analyses in human cell lines, but few have applied these techniques to human neural tissue. To gain a global molecular perspective on the role of the human genome in cortical development, function and ageing, we explore the temporal dynamics and genetic control of transcription in human prefrontal cortex in an extensive series of
Numerous genetic linkage and association reports have implicated the Disrupted-in-Schizophrenia (... more Numerous genetic linkage and association reports have implicated the Disrupted-in-Schizophrenia (DISC1) gene in psychiatric illness. The Scottish family translocation, predicted to encode a C-terminus-truncated protein, suggests involvement of short isoforms in the pathophysiology of mental disorders. We recently reported complex alternative splicing patterns for the DISC1 gene and found that short isoforms are overexpressed in the brains of patients with schizophrenia and in carriers of risk-associated alleles. Investigation into the protein-protein interactions of alternative DISC1 isoforms may provide information about the functional consequences of overexpression of truncated forms in mental illness. Human embryonic kidney (HEK293) cells were transiently co-transfected with human epitope-tagged DISC1 variants and epitope-tagged NDEL1, FEZ1, GSK3β and PDE4B constructs. Co-immunoprecipitation assays demonstrated that all truncated DISC1 variants formed complexes with full-length D...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
Rats with neonatal excitotoxic damage of the ventral hippocampus display in adulthood a variety o... more Rats with neonatal excitotoxic damage of the ventral hippocampus display in adulthood a variety of abnormalities reminiscent of schizophrenia and are used as an animal model of this disorder. In the present study, we hypothesized that transient inactivation of ventral hippocampal activity during a critical developmental period may be sufficient to disrupt normal maturation of relevant brain systems and produce similar lasting behavioral changes. We infused tetrodotoxin (TTX) or artificial CSF into the ventral hippocampus on postnatal day 7 (P7) and assessed behavioral changes in response to stress, amphetamine, and (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate in juvenile (P35) and young adult (P56) rats. In adulthood, rats infused neonatally with TTX displayed motor hyperactivity after pharmacological stimulation and after stress compared with sham controls. Analogous TTX infusions in adult animals did not alter these behaviors later in life. These data...
Proceedings of the National Academy of Sciences of the United States of America, Jan 25, 2006
Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated... more Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5' upstream region of the gene for their effects on mRNA abundance of NRG1 types I-IV in human postmortem hippocampus. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain/loss of putative binding sites for three transcription ...
Rats with excitotoxic neonatal ventral hippocampal lesions (NVHL) manifest in early adulthood a v... more Rats with excitotoxic neonatal ventral hippocampal lesions (NVHL) manifest in early adulthood a variety of behavioral and neurochemical abnormalities mimicking those seen in patients with schizophrenia. Some of these aberrations implicate malfunction of the midbrain dopamine systems. We studied NVHL effects on dopamine release in the rat frontal cortex, nucleus accumbens, and striatum during acute stress caused by inescapable continuous footshock (0.45 mA). Serum total corticosterone and prolactin levels were used as peripheral indices of stress. As an indirect index of dopamine release, tissue 3-methoxytyramine levels attained in vivo 10 min after monoamine oxidase inhibition was assayed in rats sacrificed by instantaneous microwave fixation of the brain tissue. Nonshocked NVHL rats showed significantly less nucleus accumbens' 3-methoxytyramine accumulation than their sham counterparts. Frontal cortical 3-methoxytyramine levels rose similarly after 20-min footshock in both groups of rats, but while it normalized after 60-min footshock in the sham rats, it did not decrease in the NVHL rats. Nucleus accumbens' 3-methoxytyramine was significantly elevated after either 20-min or 60-min footshock in both groups, whereas striatal 3-methoxytyramine was significantly elevated in the NVHL rats only. Serum corticosterone showed similar elevations in the sham and NVHL rats, but the patterns differed in that there was no attenuation after 60-min footshock in the latter. The lesion did not affect serum prolactin response. These data indicate that neonatal ventral hippocampal damage enhances and prolongs certain neural and neuroendocrine responses to acute physical stressor(s), and thus may affect adaptation and enhance detrimental effects of stress.
The effects of neonatal excitotoxic ventral hippocampus (VH) lesions on dopamine release in respo... more The effects of neonatal excitotoxic ventral hippocampus (VH) lesions on dopamine release in response to repeated stress (saline injections) and to chronic haloperidol treatment were investigated in Sprague-Dawley rats infused with ibotenic acid or vehicle into the VH on day 7 of postnatal life (PD7). Beginning on PD35, lesioned and sham-operated rats were injected i.p. with saline (INJ) once daily for 3 weeks or were not treated (NO INJ). Another cohort of rats was given haloperidol (HAL, 0.4 mg/kg, i.p.) or vehicle beginning on PD35 and thereafter once daily for 3 weeks. 3-Methoxytyramine (3-MT) was measured by combined gas chromatography/mass spectrometry in the frontal cortex (FC), nucleus accumbens (NAcc), and striatum (STR) at PD56 following MAO inhibition with pargyline. At baseline (NO INJ), 3-MT was reduced in STR of lesioned rats. Repeated saline injections resulted in a further 3-MT reduction in STR, FC, and NAcc of lesioned animals, but had no effect in sham rats. Chronic HAL, compared with vehicle, suppressed locomotor activity, and increased 3-MT accumulation in the FC, NAcc, and STR in sham and lesioned rats. This increase was enhanced in the FC of lesioned rats. These data show that mild repeated stress attenuates dopamine release in FC, NAcc, and STR of lesioned rats, while chronic HAL augments it in FC of lesioned animals versus controls. We conclude that the neonatal excitotoxic lesion of VH alters the functioning of midbrain dopamine systems during environmental and pharmacological challenge.
Two of the favorite hypotheses of schizophrenia research-maldevelopment of cerebral cortex and ma... more Two of the favorite hypotheses of schizophrenia research-maldevelopment of cerebral cortex and malfunction of brain dopamine systems-have often seemed difficult to reconcile. This article reviews recent research that suggests a heuristically useful reconciliation centered on the functional neuroanatomical concept of prefrontal-temporolimbic cortical connectivity. Anatomical findings from postmortem studies and neuropsychological and neuroimaging studies of brain function in patients with schizophrenia have implicated a developmental 'dysconnection' of temporolimbic-prefrontal cortices. The possibility that such dysconnection can account for the principal phenomenology of the illness, including its delayed onset and its treatment, is suggested by neurologic disease analogies such as metachromatic leukodystrophy and by recent studies in animals with developmental cortical lesions. Studies mapping neuronal gene expression indicate that all antipsychotic drugs modulate DNA transcription in a region of the nucleus accumbens that receives converging inputs from prefrontal and temporolimbic cortices, suggesting that indirect compensation for dysfunctional communication between prefrontal and temporolimbic cortices is a therapeutic mechanism of these drugs. Treatments aimed at direct cortical compensation may be more effective.
The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of sev... more The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of several aspects of schizophrenia. This lesion produces a number of behavioural abnormalities, such as hyperlocomotion and deficits in prepulse inhibition of startle, that present themselves relatively late in development, i.e. after puberty. Some of these abnormalities, which are thought to model the positive symptoms of schizophrenia, can be normalized by chronic treatment with neuroleptics. In the present study, we examined the effects of the neonatal hippocampal lesion on social behaviour. Social withdrawal and isolation are key components of the negative symptoms of schizophrenia that have not been previously addressed in this model. Rats were lesioned on postnatal day 7 (PD7) and tested for social interaction on PD35 and PD65. They were then treated with clozapine (1.9 and 7.4 micromol/kg or 0.63 and 2.5 mg/kg) for 21 days and retested. The results show that although, as previously reported, spontaneous hyperlocomotion emerged in the lesioned rats only after puberty (PD65), social interaction deficits and behaviors that may reflect anxiety were present at both PD35 and PD65. Clozapine normalized locomotion, but did not ameliorate putative anxiety or social interaction deficits in the neonatally lesioned rats. Our results indicate that the neonatal hippocampal lesion in the rat models some aspects of both positive and negative symptoms of schizophrenia. The effects of clozapine appear inconsistent with its putative benefit for negative symptoms.
This study assessed the effects of central serotonergic depletion on exploratory activity at base... more This study assessed the effects of central serotonergic depletion on exploratory activity at baseline, as well as after administration of d-amphetamine or the anxiogenic beta-carboline FG-7142. Intraventricular 5,7-dihydroxytryptamine (5,7-DHT) induced an almost complete depletion of serotonin [5-hydroxytryptamine (5-HT)] in the medial prefrontal cortex, nucleus accumbens, medial corpus striatum, and hippocampus with no changes in norepinephrine, dopamine or dihydroxyphenylacetic acid concentrations. 5-HT-depleted rats demonstrated reduced spontaneous and d-amphetamine-augmented exploration 3-10 weeks postoperatively. An effect on FG-7142-induced inhibition of exploratory activity was not apparent. These data implicate 5-HT systems in the expression of different aspects of exploratory and amphetamine-augmented motor behaviors.
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Papers by Barbara Lipska