Liat Levita | The University of Sheffield (original) (raw)

Papers by Liat Levita

Research paper thumbnail of The Darker Side of Nightmares

Research paper thumbnail of Distinct Changes in Cortical Acetylcholine and Noradrenaline Efflux during Contingent and Noncontingent Performance of a Visual Attentional Task

Optimization of cognitive processing may depend on specific and distinct functions of the cortica... more Optimization of cognitive processing may depend on specific and distinct functions of the cortical cholinergic and noradren- ergic systems. This investigation dissociates functions of cor- tical acetylcholine (ACh) and noradrenaline (NA) in arousal and visual attention by simultaneously measuring ACh and NA efflux in the rat prefrontal cortex during sustained attentional perfor- mance. The five-choice serial reaction time task was

Research paper thumbnail of Avoidance of harm and anxiety: A role for the nucleus accumbens

NeuroImage, 2012

Active and passive avoidance behaviors involve either emitting or omitting a response to avoid po... more Active and passive avoidance behaviors involve either emitting or omitting a response to avoid potential harm. Both are key components in the etiology and maintenance of anxiety disorders, yet the neural circuitry that mediates avoidance is underexplored. Using functional magnetic resonance imaging greater hemodynamic activation of the nucleus accumbens was found during active avoidance, whereas greater deactivation of the nucleus accumbens was observed during passive avoidance. These findings extend the role of the NAcc from purely reward-based action-contingencies, to one that also involves either emitting or withholding a response to avoid harm. Critically, the degree of activation and deactivation of the NAcc during avoidance was associated with individual levels of anxiety, which supports the idea that the NAcc may play a key role in the etiology and maintenance of aberrant avoidance behaviors in disorders of anxiety.

Research paper thumbnail of A Genetic Variant BDNF Polymorphism Alters Extinction Learning in Both Mouse and Human

Science, 2010

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).

Research paper thumbnail of 5-hydroxytryptamine1a-likereceptor activation in the bed nucleus of the stria terminalis: Electrophysiological and behavioral studies

Neuroscience, 2004

The anteriorlateral bed nucleus of the stria terminalis (BNST AL ) and the serotonergic system ar... more The anteriorlateral bed nucleus of the stria terminalis (BNST AL ) and the serotonergic system are believed to modulate behavioral responses to stressful and/or anxiogenic stimuli. However, although the BNST AL receives heavy serotonergic innervation, the functional significance of this input is not known. Data obtained from in vitro whole-cell patch clamp recording in the rat BNST slice show that exogenous application of 5-hydroxytryptamine (5-HT) evoked a heterogeneous response in BNST AL neurons. The principal action of 5-HT in this region was inhibitory, evoking a membrane hyperpolarization (5-HT Hyp ) and a concomitant reduction in input resistance in the majority of neurons tested. The broad-spectrum 5-HT 1 agonist, 5-carboxamindotryptamine (5-CT), but not R(؎)8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), mimicked the 5-HT Hyp response in the BNST. Moreover, the outward current mediating 5-HT Hyp was inwardly rectifying and sensitive to the G protein activated inwardly rectifying K ؉ (G IRK ) channel blocker, tertiapin-Q. In the CNS 5-HT 1A receptors are thought to couple to G IRK channels, suggesting that 5-HT Hyp in BNST AL neurons was mediated by activation of 5-HT 1A-like receptors. This was confirmed by the blockade of both 5-HT Hyp and 5-CT Hyp by the specific 5-HT 1A receptor antagonist N-[2-[4-(2methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY100635 200nM). Furthermore, an in vivo examination of the functional consequences of 5-HT 1A-like induced inhibition of BNST neurons revealed that infusion of 5-CT into the BNST significantly reduced the acoustic startle response, without affecting the general motor activity of the animals. These data point to the possibility that 5-HT 1A mediated inhibition of the BNST AL could contribute to an anxiolytic action. Hence, we propose that in response to stressful stimuli, enhanced levels of 5-HT in the BNST AL plays a critical homeostatic role in feedback inhibition of the anxiogenic response to these stimuli. (D. Rainnie). Abbreviations: ACSF, artificial cerebrospinal fluid; BNST, bed nucleus of the stria terminalis; BNST AL , anteriorlateral bed nucleus of the stria terminalis; CGP 52432, 3-[[3,4-dichlorophenyl)methyl]amino]propyl] diethoxymethyl)phosphinic acid; DAB, 3,3=-diaminobenzidine; E 5-HT , reversal potential of 5-HT; G IRK , G protein-activated inwardly rectifying K ϩ channels; ISI, interstimulus interval; LTDg, lateral tegmental nucleus; PnC, nucleus reticularis pontis caudalis; PPTg, pedunculopontine tegmental nucleus; Rm, input resistance; TTX, tetrodotoxin; WAY100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt; 5-CT, 5-carboxamidotryptamine; 5-CT Hyp , 5-CT-evoked membrane hyperpolarization; 5-HT, 5-hydroxytryptamine; 5-HT Dep , 5-HT-evoked membrane depolarization; 5-HT Hyp , 5-HT-evoked membrane hyperpolarization; 5-HT Hyp-Dep , 5-HT-evoked membrane hyperpolarization followed by depolarization; 8-OH-DPAT, R(Ϯ)8-hydroxydipropylaminotetralin hydrobromide.

Research paper thumbnail of Bi-directional modulation of bed nucleus of stria terminalis neurons by 5-HT: molecular expression and functional properties of excitatory 5-HT receptor subtypes

Neuroscience, 2009

Activation of neurons in the anterolateral bed nucleus of the stria terminalis (BNST ALG ) plays ... more Activation of neurons in the anterolateral bed nucleus of the stria terminalis (BNST ALG ) plays an important role in mediating the behavioral response to stressful and anxiogenic stimuli. Application of 5-HT elicits complex postsynaptic responses in BNST ALG neurons, which includes (1) membrane hyperpolarization (5-HT Hyp ), (2) hyperpolarization followed by depolarization (5-HT Hyp-Dep ), (3) depolarization (5-HT Dep ) or (4) no response (5-HT NR ). We have shown that the inhibitory response is mediated by activation of postsynaptic 5-HT 1A receptors. Here, we used a combination of in vitro whole-cell patch-clamp recording and single cell reverse transcriptase polymerase chain reaction (RT-PCR) to determine the pharmacological properties and molecular profile of 5-HT receptor subtypes mediating the excitatory response to 5-HT in BNST ALG neurons. We show that the depolarizing component of both the 5-HT Hyp/Dep and the 5-HT Dep response was mediated by activation of 5-HT 2A , 5-HT 2C and/or 5-HT 7 receptors. Single cell RT-PCR data revealed that 5-HT 7 receptors (46%) and 5-HT 1A receptors (41%) are the most prevalent receptor subtypes expressed in BNST ALG neurons. Moreover, 5-HT receptor subtypes are differentially expressed in type I-III BNST ALG neurons. Hence, 5-HT 2C receptors are almost exclusively expressed by type III neurons, whereas 5-HT 7 receptors are expressed by type I and II neurons, but not type III neurons. Conversely, 5-HT 2A receptors are found predominantly in type II neurons. Finally, bi-directional modulation of individual neurons occurs only in type I and II neurons. Significantly the distribution of 5-HT receptor subtypes in BNST ALG neurons predicted the observed expression pattern of 5-HT responses determined pharmacologically. Together, these results suggest that 5-HT can differentially modulate the excitability of type I-III neurons, and further suggest that bi-directional modulation of BNST ALG neurons occurs primarily through an interplay between 5-HT 1A and 5-HT 7 receptors. Hence, modulation of 5-HT 7 receptor activity in the BNST ALG may offer a novel avenue for the design of anxiolytic medications. (D. G. Rainnie). Abbreviations: ACSF, artificial cerebrospinal fluid; BNST, bed nucleus of stria terminalis; BNST ALG , anterolateral bed nucleus of the stria terminalis; DOI, (Ϫ)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; mCPBG, m-chlorophenylbiguanide; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase polymerase chain reaction; 5-CT, 5-carboxamidotryptamine; 5-HT Dep , 5-HT induced depolarization; 5-HT Hyp , 5-HT induced hyperpolarization; 5-HT Hyp-Dep , 5-HT induced hyperpolarization followed by depolarization; 5-HT NR , no response to 5-HT; E 5-CT , reversal potential of 5-CT response; E 5-HT , reversal potential of 5-HT response.

Research paper thumbnail of Brain-derived neurotrophic factor as a model system for examining gene by environment interactions across development

Neuroscience, 2009

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.

Research paper thumbnail of The bivalent side of the nucleus accumbens

NeuroImage, 2009

An increasing body of evidence suggests that the nucleus accumbens (NAcc) is engaged in both ince... more An increasing body of evidence suggests that the nucleus accumbens (NAcc) is engaged in both incentive reward processes and in adaptive responses to conditioned and unconditioned aversive stimuli. Yet, it has been argued that NAcc activation to aversive stimuli may be a consequence of the rewarding effects of their termination, i.e., relief. To address this question we used fMRI to delineate brain response to the onset and offset of unpleasant and pleasant auditory stimuli in the absence of learning or motor response. Increased NAcc activity was seen for the onset of both pleasant and unpleasant stimuli. Our results support the expanded bivalent view of NAcc function and call for expansion of current models of NAcc function that are solely focused on reward.

Research paper thumbnail of Nucleus accumbens dopamine and learned fear revisited: a review and some new findings

Behavioural Brain Research, 2002

A role for the nucleus accumbens (NAcc) and its dopamine (DA) innervation in fear and fear learni... more A role for the nucleus accumbens (NAcc) and its dopamine (DA) innervation in fear and fear learning is supported by a large body of evidence, which has challenged the view that the NAcc is solely involved in mediating appetitive processes. Unfortunately, due to conflicting findings in the aversive conditioning literature the role of the NAcc in aversive conditioning remains unclear. This review focuses on the results of recent in vivo microdialysis studies that have examined the release of NAcc DA during Pavlovian aversive conditioning. In addition, we present additional new findings, which re-examine the involvement of NAcc DA in aversive conditioning. DA release was measured in the NAcc core using in vivo microdialysis during discrete cue Pavlovian aversive conditioning in four experiments. In all cases no change in DA levels was observed either during training or in response to the CS presentations despite robust behavioural evidence of discrete cue Pavlovian aversive conditioning. These findings contrast with some previous studies that show that primary and conditioned aversive stimuli increase DA release in the NAcc. We suggest that the inconsistencies in the literature might be due to procedural differences in the measurement of aversive conditioning, and the precise location of the probe in the NAcc region. Hence, rather than discount an involvement of NAcc DA in affective processes, we propose that functionally dissociable sub-regions of the NAcc may contribute to different aspects of Pavlovian aversive learning. #

Research paper thumbnail of Sulpiride alleviates the attentional impairments of rats with medial prefrontal cortex lesions

Behavioural Brain Research, 2003

Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a nu... more Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a number of rodent tests of attention. Although this evidence clearly suggests a role for the rat mPFC in attentional functions, it is unclear whether subcortical changes associated with mPFC lesions might also be relevant to the neuropsychological deficits observed. Given the ample evidence suggesting increased dopaminergic mechanisms in the basal ganglia following mPFC lesions, we investigated the effects of dopamine receptor agonists and antagonists on the attentional deficits associated with mPFC lesions. Rats trained on a five-choice reaction time task received either complete mPFC lesions or lesions restricted to its ventral subregions, the prelimbic and infralimbic cortices (PRL-IL). Compared with sham-operated rats, animals in both the lesioned groups were impaired at responding correctly to the visual targets, although this deficit was more marked in mPFC-lesioned rats. In addition, both lesions were associated with increased perseverative responding. The accuracy deficits of rats with mPFC lesions were alleviated by systemic administration of the dopamine D2 receptor antagonist sulpiride. In contrast, rats with PRL-IL damage were not affected and control rats were impaired by sulpiride. Administration of either the dopamine D1 receptor antagonist SCH 23390 or of pre-synaptic doses of apomorphine had similar, albeit non-significant effects. Higher doses of any of these drugs non-specifically impaired performance. These results extend previous findings of attentional impairments in rats with mPFC lesions and are compatible with recent hypotheses concerning the role of dopaminergic dysregulation in the pathogenesis of schizophrenia. #

Research paper thumbnail of Disruption of Pavlovian contextual conditioning by excitotoxic lesions of the nucleus accumbens core

Behavioral Neuroscience, 2002

Nucleus accumbens (NAcc) core lesions were performed either before or after Pavlovian aversive co... more Nucleus accumbens (NAcc) core lesions were performed either before or after Pavlovian aversive conditioning. NAcc core lesions had no effect on discrete-cue or contextual conditioned freezing during acquisition. During retention testing, neither pre- nor posttraining lesions had any effect on conditioned freezing to the discrete cue. However, pretraining lesions resulted in a profound impairment of contextual conditioned freezing in a retention test, and posttraining lesions resulted in a smaller impairment. NAcc core lesions had no effect on sensory or motor processes, as measured by shock reactivity and spontaneous locomotor activity. These results suggest that during acquisition, processes independent of the NAcc core mediate contextual conditioned freezing, but that the NAcc is implicated in the retention of this aversive memory.

Research paper thumbnail of Linguistic Alignment in Adults with and Without Asperger’s Syndrome

Journal of Autism and Developmental Disorders, 2013

Active and passive avoidance behaviors involve either emitting or omitting a response to avoid po... more Active and passive avoidance behaviors involve either emitting or omitting a response to avoid potential harm. Both are key components in the etiology and maintenance of anxiety disorders, yet the neural circuitry that mediates avoidance is underexplored. Using functional magnetic resonance imaging greater hemodynamic activation of the nucleus accumbens was found during active avoidance, whereas greater deactivation of the nucleus accumbens was observed during passive avoidance. These findings extend the role of the NAcc from purely reward-based action-contingencies, to one that also involves either emitting or withholding a response to avoid harm. Critically, the degree of activation and deactivation of the NAcc during avoidance was associated with individual levels of anxiety, which supports the idea that the NAcc may play a key role in the etiology and maintenance of aberrant avoidance behaviors in disorders of anxiety.

Research paper thumbnail of The Darker Side of Nightmares

Research paper thumbnail of Distinct Changes in Cortical Acetylcholine and Noradrenaline Efflux during Contingent and Noncontingent Performance of a Visual Attentional Task

Optimization of cognitive processing may depend on specific and distinct functions of the cortica... more Optimization of cognitive processing may depend on specific and distinct functions of the cortical cholinergic and noradren- ergic systems. This investigation dissociates functions of cor- tical acetylcholine (ACh) and noradrenaline (NA) in arousal and visual attention by simultaneously measuring ACh and NA efflux in the rat prefrontal cortex during sustained attentional perfor- mance. The five-choice serial reaction time task was

Research paper thumbnail of Avoidance of harm and anxiety: A role for the nucleus accumbens

NeuroImage, 2012

Active and passive avoidance behaviors involve either emitting or omitting a response to avoid po... more Active and passive avoidance behaviors involve either emitting or omitting a response to avoid potential harm. Both are key components in the etiology and maintenance of anxiety disorders, yet the neural circuitry that mediates avoidance is underexplored. Using functional magnetic resonance imaging greater hemodynamic activation of the nucleus accumbens was found during active avoidance, whereas greater deactivation of the nucleus accumbens was observed during passive avoidance. These findings extend the role of the NAcc from purely reward-based action-contingencies, to one that also involves either emitting or withholding a response to avoid harm. Critically, the degree of activation and deactivation of the NAcc during avoidance was associated with individual levels of anxiety, which supports the idea that the NAcc may play a key role in the etiology and maintenance of aberrant avoidance behaviors in disorders of anxiety.

Research paper thumbnail of A Genetic Variant BDNF Polymorphism Alters Extinction Learning in Both Mouse and Human

Science, 2010

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).

Research paper thumbnail of 5-hydroxytryptamine1a-likereceptor activation in the bed nucleus of the stria terminalis: Electrophysiological and behavioral studies

Neuroscience, 2004

The anteriorlateral bed nucleus of the stria terminalis (BNST AL ) and the serotonergic system ar... more The anteriorlateral bed nucleus of the stria terminalis (BNST AL ) and the serotonergic system are believed to modulate behavioral responses to stressful and/or anxiogenic stimuli. However, although the BNST AL receives heavy serotonergic innervation, the functional significance of this input is not known. Data obtained from in vitro whole-cell patch clamp recording in the rat BNST slice show that exogenous application of 5-hydroxytryptamine (5-HT) evoked a heterogeneous response in BNST AL neurons. The principal action of 5-HT in this region was inhibitory, evoking a membrane hyperpolarization (5-HT Hyp ) and a concomitant reduction in input resistance in the majority of neurons tested. The broad-spectrum 5-HT 1 agonist, 5-carboxamindotryptamine (5-CT), but not R(؎)8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT), mimicked the 5-HT Hyp response in the BNST. Moreover, the outward current mediating 5-HT Hyp was inwardly rectifying and sensitive to the G protein activated inwardly rectifying K ؉ (G IRK ) channel blocker, tertiapin-Q. In the CNS 5-HT 1A receptors are thought to couple to G IRK channels, suggesting that 5-HT Hyp in BNST AL neurons was mediated by activation of 5-HT 1A-like receptors. This was confirmed by the blockade of both 5-HT Hyp and 5-CT Hyp by the specific 5-HT 1A receptor antagonist N-[2-[4-(2methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY100635 200nM). Furthermore, an in vivo examination of the functional consequences of 5-HT 1A-like induced inhibition of BNST neurons revealed that infusion of 5-CT into the BNST significantly reduced the acoustic startle response, without affecting the general motor activity of the animals. These data point to the possibility that 5-HT 1A mediated inhibition of the BNST AL could contribute to an anxiolytic action. Hence, we propose that in response to stressful stimuli, enhanced levels of 5-HT in the BNST AL plays a critical homeostatic role in feedback inhibition of the anxiogenic response to these stimuli. (D. Rainnie). Abbreviations: ACSF, artificial cerebrospinal fluid; BNST, bed nucleus of the stria terminalis; BNST AL , anteriorlateral bed nucleus of the stria terminalis; CGP 52432, 3-[[3,4-dichlorophenyl)methyl]amino]propyl] diethoxymethyl)phosphinic acid; DAB, 3,3=-diaminobenzidine; E 5-HT , reversal potential of 5-HT; G IRK , G protein-activated inwardly rectifying K ϩ channels; ISI, interstimulus interval; LTDg, lateral tegmental nucleus; PnC, nucleus reticularis pontis caudalis; PPTg, pedunculopontine tegmental nucleus; Rm, input resistance; TTX, tetrodotoxin; WAY100635, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt; 5-CT, 5-carboxamidotryptamine; 5-CT Hyp , 5-CT-evoked membrane hyperpolarization; 5-HT, 5-hydroxytryptamine; 5-HT Dep , 5-HT-evoked membrane depolarization; 5-HT Hyp , 5-HT-evoked membrane hyperpolarization; 5-HT Hyp-Dep , 5-HT-evoked membrane hyperpolarization followed by depolarization; 8-OH-DPAT, R(Ϯ)8-hydroxydipropylaminotetralin hydrobromide.

Research paper thumbnail of Bi-directional modulation of bed nucleus of stria terminalis neurons by 5-HT: molecular expression and functional properties of excitatory 5-HT receptor subtypes

Neuroscience, 2009

Activation of neurons in the anterolateral bed nucleus of the stria terminalis (BNST ALG ) plays ... more Activation of neurons in the anterolateral bed nucleus of the stria terminalis (BNST ALG ) plays an important role in mediating the behavioral response to stressful and anxiogenic stimuli. Application of 5-HT elicits complex postsynaptic responses in BNST ALG neurons, which includes (1) membrane hyperpolarization (5-HT Hyp ), (2) hyperpolarization followed by depolarization (5-HT Hyp-Dep ), (3) depolarization (5-HT Dep ) or (4) no response (5-HT NR ). We have shown that the inhibitory response is mediated by activation of postsynaptic 5-HT 1A receptors. Here, we used a combination of in vitro whole-cell patch-clamp recording and single cell reverse transcriptase polymerase chain reaction (RT-PCR) to determine the pharmacological properties and molecular profile of 5-HT receptor subtypes mediating the excitatory response to 5-HT in BNST ALG neurons. We show that the depolarizing component of both the 5-HT Hyp/Dep and the 5-HT Dep response was mediated by activation of 5-HT 2A , 5-HT 2C and/or 5-HT 7 receptors. Single cell RT-PCR data revealed that 5-HT 7 receptors (46%) and 5-HT 1A receptors (41%) are the most prevalent receptor subtypes expressed in BNST ALG neurons. Moreover, 5-HT receptor subtypes are differentially expressed in type I-III BNST ALG neurons. Hence, 5-HT 2C receptors are almost exclusively expressed by type III neurons, whereas 5-HT 7 receptors are expressed by type I and II neurons, but not type III neurons. Conversely, 5-HT 2A receptors are found predominantly in type II neurons. Finally, bi-directional modulation of individual neurons occurs only in type I and II neurons. Significantly the distribution of 5-HT receptor subtypes in BNST ALG neurons predicted the observed expression pattern of 5-HT responses determined pharmacologically. Together, these results suggest that 5-HT can differentially modulate the excitability of type I-III neurons, and further suggest that bi-directional modulation of BNST ALG neurons occurs primarily through an interplay between 5-HT 1A and 5-HT 7 receptors. Hence, modulation of 5-HT 7 receptor activity in the BNST ALG may offer a novel avenue for the design of anxiolytic medications. (D. G. Rainnie). Abbreviations: ACSF, artificial cerebrospinal fluid; BNST, bed nucleus of stria terminalis; BNST ALG , anterolateral bed nucleus of the stria terminalis; DOI, (Ϫ)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; mCPBG, m-chlorophenylbiguanide; PCR, polymerase chain reaction; RT-PCR, reverse transcriptase polymerase chain reaction; 5-CT, 5-carboxamidotryptamine; 5-HT Dep , 5-HT induced depolarization; 5-HT Hyp , 5-HT induced hyperpolarization; 5-HT Hyp-Dep , 5-HT induced hyperpolarization followed by depolarization; 5-HT NR , no response to 5-HT; E 5-CT , reversal potential of 5-CT response; E 5-HT , reversal potential of 5-HT response.

Research paper thumbnail of Brain-derived neurotrophic factor as a model system for examining gene by environment interactions across development

Neuroscience, 2009

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.

Research paper thumbnail of The bivalent side of the nucleus accumbens

NeuroImage, 2009

An increasing body of evidence suggests that the nucleus accumbens (NAcc) is engaged in both ince... more An increasing body of evidence suggests that the nucleus accumbens (NAcc) is engaged in both incentive reward processes and in adaptive responses to conditioned and unconditioned aversive stimuli. Yet, it has been argued that NAcc activation to aversive stimuli may be a consequence of the rewarding effects of their termination, i.e., relief. To address this question we used fMRI to delineate brain response to the onset and offset of unpleasant and pleasant auditory stimuli in the absence of learning or motor response. Increased NAcc activity was seen for the onset of both pleasant and unpleasant stimuli. Our results support the expanded bivalent view of NAcc function and call for expansion of current models of NAcc function that are solely focused on reward.

Research paper thumbnail of Nucleus accumbens dopamine and learned fear revisited: a review and some new findings

Behavioural Brain Research, 2002

A role for the nucleus accumbens (NAcc) and its dopamine (DA) innervation in fear and fear learni... more A role for the nucleus accumbens (NAcc) and its dopamine (DA) innervation in fear and fear learning is supported by a large body of evidence, which has challenged the view that the NAcc is solely involved in mediating appetitive processes. Unfortunately, due to conflicting findings in the aversive conditioning literature the role of the NAcc in aversive conditioning remains unclear. This review focuses on the results of recent in vivo microdialysis studies that have examined the release of NAcc DA during Pavlovian aversive conditioning. In addition, we present additional new findings, which re-examine the involvement of NAcc DA in aversive conditioning. DA release was measured in the NAcc core using in vivo microdialysis during discrete cue Pavlovian aversive conditioning in four experiments. In all cases no change in DA levels was observed either during training or in response to the CS presentations despite robust behavioural evidence of discrete cue Pavlovian aversive conditioning. These findings contrast with some previous studies that show that primary and conditioned aversive stimuli increase DA release in the NAcc. We suggest that the inconsistencies in the literature might be due to procedural differences in the measurement of aversive conditioning, and the precise location of the probe in the NAcc region. Hence, rather than discount an involvement of NAcc DA in affective processes, we propose that functionally dissociable sub-regions of the NAcc may contribute to different aspects of Pavlovian aversive learning. #

Research paper thumbnail of Sulpiride alleviates the attentional impairments of rats with medial prefrontal cortex lesions

Behavioural Brain Research, 2003

Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a nu... more Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a number of rodent tests of attention. Although this evidence clearly suggests a role for the rat mPFC in attentional functions, it is unclear whether subcortical changes associated with mPFC lesions might also be relevant to the neuropsychological deficits observed. Given the ample evidence suggesting increased dopaminergic mechanisms in the basal ganglia following mPFC lesions, we investigated the effects of dopamine receptor agonists and antagonists on the attentional deficits associated with mPFC lesions. Rats trained on a five-choice reaction time task received either complete mPFC lesions or lesions restricted to its ventral subregions, the prelimbic and infralimbic cortices (PRL-IL). Compared with sham-operated rats, animals in both the lesioned groups were impaired at responding correctly to the visual targets, although this deficit was more marked in mPFC-lesioned rats. In addition, both lesions were associated with increased perseverative responding. The accuracy deficits of rats with mPFC lesions were alleviated by systemic administration of the dopamine D2 receptor antagonist sulpiride. In contrast, rats with PRL-IL damage were not affected and control rats were impaired by sulpiride. Administration of either the dopamine D1 receptor antagonist SCH 23390 or of pre-synaptic doses of apomorphine had similar, albeit non-significant effects. Higher doses of any of these drugs non-specifically impaired performance. These results extend previous findings of attentional impairments in rats with mPFC lesions and are compatible with recent hypotheses concerning the role of dopaminergic dysregulation in the pathogenesis of schizophrenia. #

Research paper thumbnail of Disruption of Pavlovian contextual conditioning by excitotoxic lesions of the nucleus accumbens core

Behavioral Neuroscience, 2002

Nucleus accumbens (NAcc) core lesions were performed either before or after Pavlovian aversive co... more Nucleus accumbens (NAcc) core lesions were performed either before or after Pavlovian aversive conditioning. NAcc core lesions had no effect on discrete-cue or contextual conditioned freezing during acquisition. During retention testing, neither pre- nor posttraining lesions had any effect on conditioned freezing to the discrete cue. However, pretraining lesions resulted in a profound impairment of contextual conditioned freezing in a retention test, and posttraining lesions resulted in a smaller impairment. NAcc core lesions had no effect on sensory or motor processes, as measured by shock reactivity and spontaneous locomotor activity. These results suggest that during acquisition, processes independent of the NAcc core mediate contextual conditioned freezing, but that the NAcc is implicated in the retention of this aversive memory.

Research paper thumbnail of Linguistic Alignment in Adults with and Without Asperger’s Syndrome

Journal of Autism and Developmental Disorders, 2013

Active and passive avoidance behaviors involve either emitting or omitting a response to avoid po... more Active and passive avoidance behaviors involve either emitting or omitting a response to avoid potential harm. Both are key components in the etiology and maintenance of anxiety disorders, yet the neural circuitry that mediates avoidance is underexplored. Using functional magnetic resonance imaging greater hemodynamic activation of the nucleus accumbens was found during active avoidance, whereas greater deactivation of the nucleus accumbens was observed during passive avoidance. These findings extend the role of the NAcc from purely reward-based action-contingencies, to one that also involves either emitting or withholding a response to avoid harm. Critically, the degree of activation and deactivation of the NAcc during avoidance was associated with individual levels of anxiety, which supports the idea that the NAcc may play a key role in the etiology and maintenance of aberrant avoidance behaviors in disorders of anxiety.