Neurotrophins, which include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF),... more Neurotrophins, which include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), are a unique family of polypeptide growth factors, present in all vertebrate species, that influence the proliferation, differentiation, and survival of neuronal cells. These proteins are evolutionarily young and do not exist in invertebrate species such as Drosophila melanogaster or Caenorhabditis elegans. The late evolutionary appearance of neurotrophins implies that these signaling molecules may be necessary for both the development and functioning of a more complex nervous system (Beck et al., 2004; Chao, 2000). The efficacy of neurotrophins is dependent on their level of availability, appropriate sorting and release, and their binding affinity to transmembrane receptors. Neurotrophins were initially identified as signaling molecules that are critical in the development of the nervous system. Transgenic mice deficient in any of the neurotrophins (with the exception of NT-4) exhibit early postnatal death. Recently, advances have been madethrough the generation of transgenic conditional knockout animals-showing that neurotrophins continue to be important in the functioning of the adult central nervous system (CNS). These genetic manipulations, which allow the gene to remain active in the developing animal and be deleted in adulthood, have shown that these proteins have a potent effect on higher order processes, such as learning and memory, later in life. Neurotrophin Ligands Neurotrophins are a recent addition to the previously known polypeptide factors that affect the survival, growth, and differentiation of cells in the nervous system. The neurotrophins comprise NGF, BDNF, NT-3, and NT-4, each of which has been shown to serve multiple functions in the development and maintenance of the nervous system (Figure 1). NGF is predominantly expressed in the peripheral nervous system in sensory and sympathetic neurons, with discrete expression in the CNS in cholinergic neurons in the basal forebrain. BDNF and NT-3 are highly expressed in CNS structures, including the cortex, the hippocampus, the limbic structures, the cerebellum, and the olfactory bulb (Huang & Reichardt, 2001; Vigers, Baquet, & Jones, 2000; Yan et al., 1997). NT-4 is also widely expressed in the CNS but is found in significantly lower levels than are BDNF and NT-3. The neurotrophins are synthesized from a 32 kDa precursor protein known as proneurotrophin, which binds with high affinity to the p75 NTR neurotrophin recep-79
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of o... more Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms 1,2 . Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD 3,4 . However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component . Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5 −/− mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.
Acknowledgments:This work was supported in part by P50 MH079513 and R01 MH73175 to BJC, R01 NS052... more Acknowledgments:This work was supported in part by P50 MH079513 and R01 MH73175 to BJC, R01 NS052819 to FSL, Hartwell Foundation Award to CEG, and a generous gift from the Dewitt-Wallace Fund and Mortimer D. Sackler family. ,, ABBREVIATIONS
A common single-nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gen... more A common single-nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNF(MET/Met)) that reproduces the phenotypic hallmarks in humans with the variant allele. Variant BDNF(Met) was expressed in brain at normal levels, but its secretion from neurons was defective. In this context, the BDNF(Met/Met) mouse represents a unique model that directly links altered activity-dependent release of BDNF to a defined set of in vivo consequences. Our subsequent analyses of these mice elucidated a phenotype that had not been established in human carriers: increased anxiety. When placed in conflict settings, BDNF(Met/Met) mice display increased anxiety-related behaviours that were not normalized by the antidepressant, fluoxetine. A genetic variant BDNF...
Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanis... more Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF, which binds p75(NTR). In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75(NTR). Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically ...
Pathological or in vitro over expression of the truncated TrkB.T1 receptor inhibits signaling thr... more Pathological or in vitro over expression of the truncated TrkB.T1 receptor inhibits signaling through the full-length TrkB (TrkB.FL) tyrosine kinase receptor. However, to date, the role of endogenous TrkB.T1 is still unknown. By studying mice lacking the truncated TrkB.T1 isoform but retaining normal spatio-temporal expression of TrkB.FL we have analyzed TrkB.T1 specific physiological functions and its effect on endogenous TrkB kinase signaling in vivo. We found that TrkB.T1 deficient mice develop normally but show increased anxiety in association with morphological abnormalities in the length and complexity of neurites of neurons in the basolateral amygdala. However, no behavioral abnormalities were detected in hippocampal-dependent memory tasks, which correlated with lack of any obvious hippocampal morphological deficits or alterations in basal synaptic transmission and Long-Term Potentiation (LTP). In vivo reduction of TrkB signaling by removal of one BDNF allele could be partially rescued by TrkB.T1 deletion, which was revealed by an amelioration of the enhanced aggression and weight gain associated to BDNF haploinsufficiency. Our results suggest that at the physiological level, TrkB.T1 receptors are important regulators of TrkB.FL signaling in vivo. Moreover, TrkB.T1 selectively affects dendrite complexity of certain neuronal populations.
Conflict has been proposed to act as a cost in action selection, implying a general function of m... more Conflict has been proposed to act as a cost in action selection, implying a general function of medio-frontal cortex in the adaptation to aversive events. Here we investigate if response conflict acts as a cost during reinforcement learning by modulating experienced reward values in cortical and striatal systems. Electroencephalography recordings show that conflict diminishes the relationship between reward-related frontal theta power and cue preference yet it enhances the relationship between punishment and cue avoidance. Individual differences in the cost of conflict on reward versus punishment sensitivity are also related to a genetic polymorphism associated with striatal D1 versus D2 pathway balance (DARPP-32). We manipulate these patterns with the D2 agent cabergoline, which induces a strong bias to amplify the aversive value of punishment outcomes following conflict. Collectively, these findings demonstrate that interactive cortico-striatal systems implicitly modulate experien...
Brain derived neurotrophic factor (BDNF) plays important roles in activity dependent plasticity p... more Brain derived neurotrophic factor (BDNF) plays important roles in activity dependent plasticity processes such as long-term potentiation, learning, and memory. The recently reported human BDNF Val66Met (BDNF Met ) polymorphism has been shown to lead to altered hippocampal volume and impaired hippocampal-dependent memory and is associated with a variety of neuropsychiatric disorders. There are few studies, however, that investigate the effect of the BDNF Met polymorphism on hippocampal-independent memory processes. A conditioned taste aversion (CTA) task was employed for studying the mechanisms of long-term, hippocampal-independent, nondeclarative memory in the mammalian brain. Using the CTA paradigm, we found a novel impairment in extinction learning, but not acquisition or retention, of aversive memories resulting from the variant BDNF Met . BDNF Met mice were slower to extinguish an aversive CTA memory compared to wildtype counterparts. Moreover, the BDNF Met was associated with smaller volume and decreased neuronal dendritic complexity in the ventromedial prefrontal cortex (vmPFC), which plays a significant role in extinction of CTA. Finally, this delay in extinction learning could be rescued pharmacologically with a cognitive enhancer, D-cycloserine (DCS). To our knowledge, this is the first evidence that the BDNF Met polymorphism contributes to abnormalities in memory extinction. This abnormality in extinction learning may be explained by alterations in neuronal morphology, as well as decreased neural activity in the vmPFC. Importantly, DCS was effective in rescuing this delay in extinction, suggesting that when coupled with behavior therapy, DCS may be an effective treatment option for anxiety disorders in humans with this genetic variant BDNF.
Presynaptic CaV2.2 channels are targets of neurotransmitters and drugs that activate G-protein co... more Presynaptic CaV2.2 channels are targets of neurotransmitters and drugs that activate G-protein coupled receptors (GPCR) to down regulate neurotransmission. In previous studies, we found that two alternatively spliced, mutually exclusive exons (e37a and e37b) control Gi/oPCR inhibition. We showed that both e37a and e37b containing CaV2.2 channels are expressed in nociceptors of dorsal root ganglia and that mice lacking e37a show reduced spinal morphine analgesia, consistent with reduced inhibition of presynaptic CaV2.2 channels via μ-opioid receptor (Gi/oPCR). We know that e37a isoforms of CaV2.2 are expressed in certain regions of the brain, leading us to assess behavior of mice that lack e37a. Here we report that mice lacking e37a isoform exhibit a robust reduced anxiety-like phenotype as compared to WT. E37a lacking mice showed significantly shorter latency times to drink in the novelty-induced hypophagia test (57.2 ± 11.9 s, n = 13) compared to WT mice (116.6 ± 22.8 s, n = 16 (p ...
The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defec... more The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF Met/Met mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in N-methyl-D-aspartic acid (NMDA) receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF Met/Met mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF Met/Met mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.
MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast,... more MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a sig...
Chronic restraint stress (CRS) induces the remodeling (i.e. retraction and simplification) of the... more Chronic restraint stress (CRS) induces the remodeling (i.e. retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activitydependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to 3 weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF +/-) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF +/mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites.
A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a m... more A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNF Met/Met ) that reproduces the phenotypic hallmarks in humans with the variant allele. BDNF Met was expressed in brain at normal levels, but its secretion from neurons was defective. When placed in stressful settings, BDNF Met/Met mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.
Conflict has been proposed to act as a cost in action selection, implying a general function of m... more Conflict has been proposed to act as a cost in action selection, implying a general function of medio-frontal cortex in the adaptation to aversive events. Here we investigate if response conflict acts as a cost during reinforcement learning by modulating experienced reward values in cortical and striatal systems. Electroencephalography recordings show that conflict diminishes the relationship between reward-related frontal theta power and cue preference yet it enhances the relationship between punishment and cue avoidance. Individual differences in the cost of conflict on reward versus punishment sensitivity are also related to a genetic polymorphism associated with striatal D1 versus D2 pathway balance (DARPP-32). We manipulate these patterns with the D2 agent cabergoline, which induces a strong bias to amplify the aversive value of punishment outcomes following conflict. Collectively, these findings demonstrate that interactive cortico-striatal systems implicitly modulate experienced reward and punishment values as a function of conflict.
identical MIS 5e/5a relative sea-level histories of tectonically stable Bermuda and Mallorca. The... more identical MIS 5e/5a relative sea-level histories of tectonically stable Bermuda and Mallorca. The very rapid onset and relatively brief nature of the MIS 5a highstand may have plausibly generated lags between the timing of sea-level changes and the timing of coral reef growth, and may provide a partial explanation as to why reefs on Barbados and New Guinea do not record a comparable eustatic height for this event. This and other factors that could be part of the apparent discrepancy are discussed in (9).
Proceedings of the National Academy of Sciences, 2011
Highly conserved neural circuitry between rodents and humans has allowed for in-depth characteriz... more Highly conserved neural circuitry between rodents and humans has allowed for in-depth characterization of behavioral and molecular processes associated with emotional learning and memory. Despite increased prevalence of affective disorders in adolescent humans, few studies have characterized how associativeemotional learning changes during the transition through adolescence or identified mechanisms underlying such changes. By examining fear conditioning in mice, as they transitioned into and out of adolescence, we found that a suppression of contextual fear occurs during adolescence. Although contextual fear memories were not expressed during early adolescence, they could be retrieved and expressed as the mice transitioned out of adolescence. This temporary suppression of contextual fear was associated with blunted synaptic activity in the basal amygdala and decreased PI3K and MAPK signaling in the hippocampus. These findings reveal a unique form of brain plasticity in fear learning during early adolescence and may prove informative for understanding endogenous mechanisms to suppress unwanted fear memories.
There has been a dramatic rise in gene؋environment studies of human behavior over the past decade... more There has been a dramatic rise in gene؋environment studies of human behavior over the past decade that have moved the field beyond simple nature versus nurture debates. These studies offer promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. Yet, it is rare that these studies consider how these interactions change over the course of development. In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene-environment interactions across development in humans.
Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) ... more Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRIinduced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF Val/Val ) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF Met/Met ). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF Met/Met mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF Met/Met mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of o... more Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms 1,2 . Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD 3,4 . However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component . Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5 −/− mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.
Acknowledgments:This work was supported in part by P50 MH079513 and R01 MH73175 to BJC, R01 NS052... more Acknowledgments:This work was supported in part by P50 MH079513 and R01 MH73175 to BJC, R01 NS052819 to FSL, Hartwell Foundation Award to CEG, and a generous gift from the Dewitt-Wallace Fund and Mortimer D. Sackler family. ,, ABBREVIATIONS
Neurotrophins, which include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF),... more Neurotrophins, which include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), are a unique family of polypeptide growth factors, present in all vertebrate species, that influence the proliferation, differentiation, and survival of neuronal cells. These proteins are evolutionarily young and do not exist in invertebrate species such as Drosophila melanogaster or Caenorhabditis elegans. The late evolutionary appearance of neurotrophins implies that these signaling molecules may be necessary for both the development and functioning of a more complex nervous system (Beck et al., 2004; Chao, 2000). The efficacy of neurotrophins is dependent on their level of availability, appropriate sorting and release, and their binding affinity to transmembrane receptors. Neurotrophins were initially identified as signaling molecules that are critical in the development of the nervous system. Transgenic mice deficient in any of the neurotrophins (with the exception of NT-4) exhibit early postnatal death. Recently, advances have been madethrough the generation of transgenic conditional knockout animals-showing that neurotrophins continue to be important in the functioning of the adult central nervous system (CNS). These genetic manipulations, which allow the gene to remain active in the developing animal and be deleted in adulthood, have shown that these proteins have a potent effect on higher order processes, such as learning and memory, later in life. Neurotrophin Ligands Neurotrophins are a recent addition to the previously known polypeptide factors that affect the survival, growth, and differentiation of cells in the nervous system. The neurotrophins comprise NGF, BDNF, NT-3, and NT-4, each of which has been shown to serve multiple functions in the development and maintenance of the nervous system (Figure 1). NGF is predominantly expressed in the peripheral nervous system in sensory and sympathetic neurons, with discrete expression in the CNS in cholinergic neurons in the basal forebrain. BDNF and NT-3 are highly expressed in CNS structures, including the cortex, the hippocampus, the limbic structures, the cerebellum, and the olfactory bulb (Huang & Reichardt, 2001; Vigers, Baquet, & Jones, 2000; Yan et al., 1997). NT-4 is also widely expressed in the CNS but is found in significantly lower levels than are BDNF and NT-3. The neurotrophins are synthesized from a 32 kDa precursor protein known as proneurotrophin, which binds with high affinity to the p75 NTR neurotrophin recep-79
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of o... more Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms 1,2 . Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD 3,4 . However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component . Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5 −/− mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.
Acknowledgments:This work was supported in part by P50 MH079513 and R01 MH73175 to BJC, R01 NS052... more Acknowledgments:This work was supported in part by P50 MH079513 and R01 MH73175 to BJC, R01 NS052819 to FSL, Hartwell Foundation Award to CEG, and a generous gift from the Dewitt-Wallace Fund and Mortimer D. Sackler family. ,, ABBREVIATIONS
A common single-nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gen... more A common single-nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNF(MET/Met)) that reproduces the phenotypic hallmarks in humans with the variant allele. Variant BDNF(Met) was expressed in brain at normal levels, but its secretion from neurons was defective. In this context, the BDNF(Met/Met) mouse represents a unique model that directly links altered activity-dependent release of BDNF to a defined set of in vivo consequences. Our subsequent analyses of these mice elucidated a phenotype that had not been established in human carriers: increased anxiety. When placed in conflict settings, BDNF(Met/Met) mice display increased anxiety-related behaviours that were not normalized by the antidepressant, fluoxetine. A genetic variant BDNF...
Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanis... more Experience-dependent plasticity shapes postnatal development of neural circuits, but the mechanisms that refine dendritic arbors, remodel spines, and impair synaptic activity are poorly understood. Mature brain-derived neurotrophic factor (BDNF) modulates neuronal morphology and synaptic plasticity, including long-term potentiation (LTP) via TrkB activation. BDNF is initially translated as proBDNF, which binds p75(NTR). In vitro, recombinant proBDNF modulates neuronal structure and alters hippocampal long-term plasticity, but the actions of endogenously expressed proBDNF are unclear. Therefore, we generated a cleavage-resistant probdnf knockin mouse. Our results demonstrate that proBDNF negatively regulates hippocampal dendritic complexity and spine density through p75(NTR). Hippocampal slices from probdnf mice exhibit depressed synaptic transmission, impaired LTP, and enhanced long-term depression (LTD) in area CA1. These results suggest that proBDNF acts in vivo as a biologically ...
Pathological or in vitro over expression of the truncated TrkB.T1 receptor inhibits signaling thr... more Pathological or in vitro over expression of the truncated TrkB.T1 receptor inhibits signaling through the full-length TrkB (TrkB.FL) tyrosine kinase receptor. However, to date, the role of endogenous TrkB.T1 is still unknown. By studying mice lacking the truncated TrkB.T1 isoform but retaining normal spatio-temporal expression of TrkB.FL we have analyzed TrkB.T1 specific physiological functions and its effect on endogenous TrkB kinase signaling in vivo. We found that TrkB.T1 deficient mice develop normally but show increased anxiety in association with morphological abnormalities in the length and complexity of neurites of neurons in the basolateral amygdala. However, no behavioral abnormalities were detected in hippocampal-dependent memory tasks, which correlated with lack of any obvious hippocampal morphological deficits or alterations in basal synaptic transmission and Long-Term Potentiation (LTP). In vivo reduction of TrkB signaling by removal of one BDNF allele could be partially rescued by TrkB.T1 deletion, which was revealed by an amelioration of the enhanced aggression and weight gain associated to BDNF haploinsufficiency. Our results suggest that at the physiological level, TrkB.T1 receptors are important regulators of TrkB.FL signaling in vivo. Moreover, TrkB.T1 selectively affects dendrite complexity of certain neuronal populations.
Conflict has been proposed to act as a cost in action selection, implying a general function of m... more Conflict has been proposed to act as a cost in action selection, implying a general function of medio-frontal cortex in the adaptation to aversive events. Here we investigate if response conflict acts as a cost during reinforcement learning by modulating experienced reward values in cortical and striatal systems. Electroencephalography recordings show that conflict diminishes the relationship between reward-related frontal theta power and cue preference yet it enhances the relationship between punishment and cue avoidance. Individual differences in the cost of conflict on reward versus punishment sensitivity are also related to a genetic polymorphism associated with striatal D1 versus D2 pathway balance (DARPP-32). We manipulate these patterns with the D2 agent cabergoline, which induces a strong bias to amplify the aversive value of punishment outcomes following conflict. Collectively, these findings demonstrate that interactive cortico-striatal systems implicitly modulate experien...
Brain derived neurotrophic factor (BDNF) plays important roles in activity dependent plasticity p... more Brain derived neurotrophic factor (BDNF) plays important roles in activity dependent plasticity processes such as long-term potentiation, learning, and memory. The recently reported human BDNF Val66Met (BDNF Met ) polymorphism has been shown to lead to altered hippocampal volume and impaired hippocampal-dependent memory and is associated with a variety of neuropsychiatric disorders. There are few studies, however, that investigate the effect of the BDNF Met polymorphism on hippocampal-independent memory processes. A conditioned taste aversion (CTA) task was employed for studying the mechanisms of long-term, hippocampal-independent, nondeclarative memory in the mammalian brain. Using the CTA paradigm, we found a novel impairment in extinction learning, but not acquisition or retention, of aversive memories resulting from the variant BDNF Met . BDNF Met mice were slower to extinguish an aversive CTA memory compared to wildtype counterparts. Moreover, the BDNF Met was associated with smaller volume and decreased neuronal dendritic complexity in the ventromedial prefrontal cortex (vmPFC), which plays a significant role in extinction of CTA. Finally, this delay in extinction learning could be rescued pharmacologically with a cognitive enhancer, D-cycloserine (DCS). To our knowledge, this is the first evidence that the BDNF Met polymorphism contributes to abnormalities in memory extinction. This abnormality in extinction learning may be explained by alterations in neuronal morphology, as well as decreased neural activity in the vmPFC. Importantly, DCS was effective in rescuing this delay in extinction, suggesting that when coupled with behavior therapy, DCS may be an effective treatment option for anxiety disorders in humans with this genetic variant BDNF.
Presynaptic CaV2.2 channels are targets of neurotransmitters and drugs that activate G-protein co... more Presynaptic CaV2.2 channels are targets of neurotransmitters and drugs that activate G-protein coupled receptors (GPCR) to down regulate neurotransmission. In previous studies, we found that two alternatively spliced, mutually exclusive exons (e37a and e37b) control Gi/oPCR inhibition. We showed that both e37a and e37b containing CaV2.2 channels are expressed in nociceptors of dorsal root ganglia and that mice lacking e37a show reduced spinal morphine analgesia, consistent with reduced inhibition of presynaptic CaV2.2 channels via μ-opioid receptor (Gi/oPCR). We know that e37a isoforms of CaV2.2 are expressed in certain regions of the brain, leading us to assess behavior of mice that lack e37a. Here we report that mice lacking e37a isoform exhibit a robust reduced anxiety-like phenotype as compared to WT. E37a lacking mice showed significantly shorter latency times to drink in the novelty-induced hypophagia test (57.2 ± 11.9 s, n = 13) compared to WT mice (116.6 ± 22.8 s, n = 16 (p ...
The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defec... more The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene results in a defect in regulated release of BDNF and affects episodic memory and affective behaviors. However, the precise role of the BDNF Val66Met polymorphism in hippocampal synaptic transmission and plasticity has not yet been studied. Therefore, we examined synaptic properties in the hippocampal CA3-CA1 synapses of BDNF Met/Met mice and matched wild-type mice. Although basal glutamatergic neurotransmission was normal, both young and adult mice showed a significant reduction in N-methyl-D-aspartic acid (NMDA) receptor-dependent long-term potentiation. We also found that NMDA receptor-dependent long-term depression was decreased in BDNF Met/Met mice. However, mGluR-dependent long-term depression was not affected by the BDNF Val66Met polymorphism. Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNF Met/Met mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus.
MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast,... more MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a sig...
Chronic restraint stress (CRS) induces the remodeling (i.e. retraction and simplification) of the... more Chronic restraint stress (CRS) induces the remodeling (i.e. retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activitydependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to 3 weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF +/-) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF +/mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites.
A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a m... more A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNF Met/Met ) that reproduces the phenotypic hallmarks in humans with the variant allele. BDNF Met was expressed in brain at normal levels, but its secretion from neurons was defective. When placed in stressful settings, BDNF Met/Met mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.
Conflict has been proposed to act as a cost in action selection, implying a general function of m... more Conflict has been proposed to act as a cost in action selection, implying a general function of medio-frontal cortex in the adaptation to aversive events. Here we investigate if response conflict acts as a cost during reinforcement learning by modulating experienced reward values in cortical and striatal systems. Electroencephalography recordings show that conflict diminishes the relationship between reward-related frontal theta power and cue preference yet it enhances the relationship between punishment and cue avoidance. Individual differences in the cost of conflict on reward versus punishment sensitivity are also related to a genetic polymorphism associated with striatal D1 versus D2 pathway balance (DARPP-32). We manipulate these patterns with the D2 agent cabergoline, which induces a strong bias to amplify the aversive value of punishment outcomes following conflict. Collectively, these findings demonstrate that interactive cortico-striatal systems implicitly modulate experienced reward and punishment values as a function of conflict.
identical MIS 5e/5a relative sea-level histories of tectonically stable Bermuda and Mallorca. The... more identical MIS 5e/5a relative sea-level histories of tectonically stable Bermuda and Mallorca. The very rapid onset and relatively brief nature of the MIS 5a highstand may have plausibly generated lags between the timing of sea-level changes and the timing of coral reef growth, and may provide a partial explanation as to why reefs on Barbados and New Guinea do not record a comparable eustatic height for this event. This and other factors that could be part of the apparent discrepancy are discussed in (9).
Proceedings of the National Academy of Sciences, 2011
Highly conserved neural circuitry between rodents and humans has allowed for in-depth characteriz... more Highly conserved neural circuitry between rodents and humans has allowed for in-depth characterization of behavioral and molecular processes associated with emotional learning and memory. Despite increased prevalence of affective disorders in adolescent humans, few studies have characterized how associativeemotional learning changes during the transition through adolescence or identified mechanisms underlying such changes. By examining fear conditioning in mice, as they transitioned into and out of adolescence, we found that a suppression of contextual fear occurs during adolescence. Although contextual fear memories were not expressed during early adolescence, they could be retrieved and expressed as the mice transitioned out of adolescence. This temporary suppression of contextual fear was associated with blunted synaptic activity in the basal amygdala and decreased PI3K and MAPK signaling in the hippocampus. These findings reveal a unique form of brain plasticity in fear learning during early adolescence and may prove informative for understanding endogenous mechanisms to suppress unwanted fear memories.
There has been a dramatic rise in gene؋environment studies of human behavior over the past decade... more There has been a dramatic rise in gene؋environment studies of human behavior over the past decade that have moved the field beyond simple nature versus nurture debates. These studies offer promise in accounting for more variability in behavioral and biological phenotypes than studies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. Yet, it is rare that these studies consider how these interactions change over the course of development. In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human polymorphism, to constrain the interpretation of gene-environment interactions across development in humans.
Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) ... more Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRIinduced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF Val/Val ) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF Met/Met ). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF Met/Met mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF Met/Met mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of o... more Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions, and it often encompasses anxiety and depressive symptoms 1,2 . Recently, the corticostriatal circuitry has been implicated in the pathogenesis of OCD 3,4 . However, the etiology, pathophysiology and molecular basis of OCD remain unknown. Several studies indicate that the pathogenesis of OCD has a genetic component . Here we demonstrate that loss of a neuron-specific transmembrane protein, SLIT and NTRK-like protein-5 (Slitrk5), leads to OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors, and is alleviated by the selective serotonin reuptake inhibitor fluoxetine. Slitrk5 −/− mice show selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology and alterations in glutamate receptor composition, which contribute to deficient corticostriatal neurotransmission. Thus, our studies identify Slitrk5 as an essential molecule at corticostriatal synapses and provide a new mouse model of OCD-like behaviors.
Acknowledgments:This work was supported in part by P50 MH079513 and R01 MH73175 to BJC, R01 NS052... more Acknowledgments:This work was supported in part by P50 MH079513 and R01 MH73175 to BJC, R01 NS052819 to FSL, Hartwell Foundation Award to CEG, and a generous gift from the Dewitt-Wallace Fund and Mortimer D. Sackler family. ,, ABBREVIATIONS
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