Anterior Cingulate Subregions Research Articles

Developmental Differences in a Hippocampal–Cingulate Pathway Involved in Learned Safety Following Interpersonal Trauma Exposure

Nearly 65% of youth experience trauma, and up to one-third of youth with trauma exposure face profound mental health sequelae. There remains a need to elucidate factors that contribute to psychopathology following trauma exposure, and to optimize interventions for youth who do not benefit sufficiently from existing treatments. Here, we probe safety signal learning (SSL), which is a mechanism of fear reduction that leverages learned safety to inhibit fear in the presence of threat-associated stimuli and has been shown to attenuate fear via a hippocampal-cingulate--specifically, a dorsal anterior cingulate cortex (dACC)--pathway. The present study used behavioral and task-based functional magnetic resonance imaging data to examine age-related associations between interpersonal trauma exposure and the behavioral and neural correlates (ie, activation and functional connectivity) of SSL in a group of 102 youth (aged 9-19 years; 46 female, 56 male) with (n= 52) and without (n= 50) interpersonal trauma exposure. Primary analyses examined anterior hippocampal activation and anterior hippocampus-dACC functional connectivity. Exploratory analyses examined centromedial (CMA) and laterobasal (LBA) amygdala activation and anterior hippocampal, CMA, and LBA functional connectivity with additional anterior cingulate subregions (ie, subgenual anterior cingulate cortex [sgACC] and rostral anterior cingulate cortex [rosACC]). Both youth with and without interpersonal trauma exposure successfully learned conditioned safety, which was determined by using self-report of contingency awareness. Youth with interpersonal trauma exposure (relative to youth in the comparison group) exhibited age-specific patterns of lower hippocampal activation (F2,96= 3.75, pFDR= .049, ηp2= 0.072), and, in exploratory analyses, showed heightened centromedial amygdala activation (F1,96= 5.37, pFDR= .046, ηp2= 0.053) and an age-related decrease in hippocampal-sgACC functional connectivity during SSL (F1,94= 10.68, pFDR= .015, ηp2= 0.102). We also show that hippocampal-sgACC functional connectivity mediated the association between interpersonal trauma exposure and post-traumatic stress disorder symptoms in an age-specific manner in the overall sample. Together, these findings suggest that although age- and trauma-specific differences in the neural correlates of SSL may relate to the development of psychopathology, youth with interpersonal trauma exposure demonstrate successful learning of conditioned safety over time. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. While citing references scientificall`y relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science.

Expression of synaptophysin and BDNF in the medial prefrontal cortex following early life stress and neonatal hypoxia-ischemia.

This study aims at investigating whether early stress interacts with brain injury due to neonatal hypoxia-ischemia (HI). To this end, we examined possible changes in synaptophysin (SYN) and brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (mPFC) of maternally separated rats that were subsequently exposed to a HI episode. Rat pups (n=11) were maternally separated during postnatal days 1 to 6 (3hr/day), while another group was left undisturbed (n=11). On postnatal day 7, a subgroup (n=12) from each postnatal manipulation was exposed to HI. Synaptophysin and BDNF expression was estimated in mPFC prelimbic and anterior cingulate subregions of the ipsilateral and contralateral to the occluded common carotid artery hemispheres. Maternally separated rats expressed significantly less BDNF and SYN in both hemispheres. Neonatal HI significantly reduced BDNF and SYN expression in the ipsilateral mPFC only and this reduction was not further altered by early stress. Our findings indicate the enduring negative effect of a short period of maternal separation on the expression of mPFC SYN and BDNF. They, also, reveal that the HI-associated decreases in these markers are limited to the ipsilateral mPFC and are not exacerbated by early stress. These decreases may have important functional implications given the role of prefrontal area in high-order cognition.

Myelination of Axons Corresponds with Faster Transmission Speed in the Prefrontal Cortex of Developing Male Rats.

Myelination of prefrontal circuits during adolescence is thought to lead to enhanced cognitive processing and improved behavioral control. However, while standard neuroimaging techniques commonly used in human and animal studies can measure large white matter bundles and residual conduction speed, they cannot directly measure myelination of individual axons or how fast electrical signals travel along these axons. Here we focused on a specific population of prefrontal axons to directly measure conduction velocity and myelin microstructure in developing male rats. An in vitro electrophysiological approach enabled us to isolate monosynaptic projections from the anterior branches of the corpus callosum (corpus callosum-forceps minor, CCFM) to the anterior cingulate subregion of the medial prefrontal cortex (Cg1) and to measure the speed and direction of action potentials propagating along these axons. We found that a large number of axons projecting from the CCFM to neurons in Layer V of Cg1 are ensheathed with myelin between pre-adolescence [postnatal day (PD)15] and mid-adolescence (PD43). This robust increase in axonal myelination is accompanied by a near doubling of transmission speed. As there was no age difference in the diameter of these axons, myelin is likely the driving force behind faster transmission of electrical signals in older animals. These developmental changes in axonal microstructure and physiology may extend to other axonal populations as well, and could underlie some of the improvements in cognitive processing between childhood and adolescence.

The role of medial prefrontal cortex in the working memory maintenance of one\u2019s own emotional responses

The role of medial prefrontal cortex (MPFC) in maintaining emotional information within working memory (WM) remains insufficiently investigated – with some studies suggesting this process activates MPFC and others suggesting its activity is suppressed. To reconcile these different results, we asked 26 healthy participants to complete a WM task involving the maintenance of emotional content (EWM), visual content (VWM), or no content (“rest”) after exposure to emotion-provoking images. We also assessed individual differences in emotional awareness (EA). We observed that dorsal MPFC was more active during EWM than VWM; further, relative to the rest condition, both of these WM conditions involved suppression of ventral MPFC. We also observed that the dorsal anterior cingulate subregion of dorsal MPFC was positively associated with EA. We discuss how these results may be able to reconcile the findings of previous EWM studies, and extend understanding of the relationship between MPFC, EA, and WM.

Oxytocin in the medial prefrontal cortex attenuates anxiety: Anatomical and receptor specificity and mechanism of action

Numerous studies in animals and humans have established that oxytocin (OT) reduces anxiety. In rats, the prelimbic (PL) subregion of the medial prefrontal cortex (mPFC) is among the brain areas implicated in the anxiolytic actions of OT. However, questions remain about the anatomical and receptor specificity of OT and its mechanism of action. Here we assessed whether the regulation of anxiety by mPFC OT is restricted to the PL subregion and evaluated whether oxytocin receptor (OTR) activation is required for OT to have an anxiolytic effect. We also examined whether OT interacts with GABA in the mPFC to reduce anxiety and investigated the extent to which OT in the mPFC affects activation of mPFC GABA neurons as well as neuronal activation in the amygdala, a primary target of the mPFC which is part of the neural network regulating anxiety. We found that OT reduced anxiety-like behavior when delivered to the PL, but not infralimbic or anterior cingulate subregions of the mPFC. The anxiolytic effect of OT in the PL mPFC was blocked by pretreatment with an OTR, but not a vasopressin receptor, antagonist as well as with a GABAA receptor antagonist. Lastly, administration of OT to the PL mPFC was accompanied by increased activation of GABA neurons in the PL mPFC and altered neuronal activation of the amygdala following anxiety testing. These results demonstrate that OT in the PL mPFC attenuates anxiety-related behavior and may do so by engaging GABAergic neurons which ultimately modulate downstream brain regions implicated in anxiety.

Focused microwave irradiation-assisted immunohistochemistry to study effects of ketamine on phospho-ERK expression in the mouse brain

Ketamine produces rapid and long-lasting antidepressant effects in depressive patients. Preclinical studies demonstrate that ketamine stimulates AMPA receptor transmission and activates BDNF/TrkB-Akt/ERK-mTOR signaling cascades, leading to a sustained increase in synaptic protein synthesis and strengthening of synaptic plasticity, a potential mechanism underlying the antidepressant effects. The purpose of this study was to develop an immunohistochemistry (IHC) assay to map the distribution of extracellular signal-regulated kinase (ERK) phosphorylation in the mouse brain in response to systemic ketamine treatment. We established a focused microwave irradiation-assisted IHC assay to detect phosphorylated (phospho) proteins including phospho-ERK, phospho- cAMP-response- element-binding protein (CREB), phospho- glutamate receptor 1 (GluR1) and phospho- calcium/calmodulin-dependent protein kinase II (CaMKII) with greater sensitivity and reproducibility in comparison to conventional IHC methods. A single dose of ketamine produced a robust, dose- and time-dependent increase in phospho-ERK immunoreactive (phospho-ERK-ir) neurons in the medial prefrontal cortex (mPFC) and the central nucleus of the amygdala. Phospho-ERK-ir neurons in the mPFC were primarily located in the prelimbic and anterior cingulate subregions with the morphology resembling pyramidal neurons. An increase in phospho-ERK-ir was also observed in the brainstem dorsal raphe nucleus and locus coeruleus. The NMDA GluN2B subtype receptor antagonist Ro 25-6981 increased phospho-ERK expression in the brain in a similar pattern as ketamine. In summary, we have established a sensitive and reliable focused microwave irradiation-assisted IHC assay, and defined the activation pattern of ERK, in response to systemic ketamine and Ro 25-6981 treatment, in brain regions that are potentially responsible for mediating the antidepressant effects.

Functional Reorganization of a Prefrontal Cortical Network Mediating Consolidation of Trace Eyeblink Conditioning

The medial prefrontal cortex (mPFC) has been studied for its role in various cognitive functions, but the roles of its subregions remain unclear. We performed tetrode recordings simultaneously from prelimbic (PL) and rostral (rACC) and caudal (cACC) anterior cingulate subregions of the rabbit mPFC to understand their interactions during learning and tests of remote memory retention for whisker-signaled trace eyeblink conditioning. cACC neurons exhibited an innate response to the conditioning stimulus (CS) that rapidly decreased across sessions, suggesting an attentional role for facilitating CS-US associations. rACC neurons from conditioned rabbits exhibited robust responses to the CS that decreased within each session, possibly evaluating its emotional salience. PL neurons exhibited robust persistent activity during the trace interval during tests of remote memory retention, suggesting its involvement in retrieval and execution of a consolidated response. Mechanistically, conditioning was associated with a greater percentage of persistently responsive neurons than neurons from pseudoconditioned control rabbits, and responses differed significantly between trials with and without conditioned responses. Collectively, these responses reflect a functional reorganization of neural activity within the prefrontal network from an attentional mode to one that orchestrates the retrieval and execution of the learned response.

Sex differences in emotion-related cognitive processes in irritable bowel syndrome and healthy control subjects

Greater responsiveness of emotional arousal circuits in relation to delivered visceral pain has been implicated as underlying central pain amplification in irritable bowel syndrome (IBS), with female subjects showing greater responses than male subjects. Functional magnetic resonance imaging was used to measure neural responses to an emotion recognition paradigm, using faces expressing negative emotions (fear and anger). Sex and disease differences in the connectivity of affective and modulatory cortical circuits were studied in 47 IBS (27 premenopausal female subjects) and 67 healthy control subjects (HCs; 38 premenopausal female subjects). Male subjects (IBS+HC) showed greater overall brain responses to stimuli than female subjects in prefrontal cortex, insula, and amygdala. Effective connectivity analyses identified major sex- and disease-related differences in the functioning of brain networks related to prefrontal regions, cingulate, insula, and amygdala. Male subjects had stronger connectivity between anterior cingulate subregions, amygdala, and insula, whereas female subjects had stronger connectivity to and from the prefrontal modulatory regions (medial/dorsolateral cortex). Male IBS subjects demonstrate greater engagement of cortical and affect-related brain circuitry compared to male control subjects and female subjects, when viewing faces depicting emotions previously shown to elicit greater behavioral and brain responses in male subjects.

Abrupt changes in the patterns and complexity of anterior cingulate cortex activity when food is introduced into an environment.

Foraging typically involves two distinct phases, an exploration phase where an organism explores its local environment in search of needed resources and an exploitation phase where a discovered resource is consumed. The behavior and cognitive requirements of exploration and exploitation are quite different and yet organisms can quickly and efficiently switch between them many times during a foraging bout. The present study investigated neural activity state dynamics in the anterior cingulate sub-region of the rat medial prefrontal cortex (mPFC) when a reliable food source was introduced into an environment. Distinct and largely independent states were detected using a Hidden Markov Model (HMM) when food was present or absent in the environment. Measures of neural entropy or complexity decreased when rats went from exploring the environment to exploiting a reliable food source. Exploration in the absence of food was associated with many weak activity states, while bouts of food consumption were characterized by fewer stronger states. Widespread activity state changes in the mPFC may help to inform foraging decisions and focus behavior on what is currently most prominent or valuable in the environment.

Contextual encoding by ensembles of medial prefrontal cortex neurons

Contextual representations serve to guide many aspects of behavior and influence the way stimuli or actions are encoded and interpreted. The medial prefrontal cortex (mPFC), including the anterior cingulate subregion, has been implicated in contextual encoding, yet the nature of contextual representations formed by the mPFC is unclear. Using multiple single-unit tetrode recordings in rats, we found that different activity patterns emerged in mPFC ensembles when animals moved between different environmental contexts. These differences in activity patterns were significantly larger than those observed for hippocampal ensembles. Whereas ≈11% of mPFC cells consistently preferred one environment over the other across multiple exposures to the same environments, optimal decoding (prediction) of the environmental setting occurred when the activity of up to ≈50% of all mPFC neurons was taken into account. On the other hand, population activity patterns were not identical upon repeated exposures to the very same environment. This was partly because the state of mPFC ensembles seemed to systematically shift with time, such that we could sometimes predict the change in ensemble state upon later reentry into one environment according to linear extrapolation from the time-dependent shifts observed during the first exposure. We also observed that many strongly action-selective mPFC neurons exhibited a significant degree of context-dependent modulation. These results highlight potential differences in contextual encoding schemes by the mPFC and hippocampus and suggest that the mPFC forms rich contextual representations that take into account not only sensory cues but also actions and time.

Functional mapping of the neural circuitry of rat maternal motivation: effects of site-specific transient neural inactivation.

The present review focuses on recent studies from our laboratory examining the neural circuitry subserving rat maternal motivation across postpartum. We employed a site-specific neural inactivation method by infusion of bupivacaine to map the maternal motivation circuitry using two complementary behavioural approaches: unconditioned maternal responsiveness and choice of pup- over cocaine-conditioned incentives in a concurrent pup/cocaine choice conditioned place preference task. Our findings revealed that, during the early postpartum period, distinct brain structures, including the medial preoptic area, ventral tegmental area and medial prefrontal cortex infralimbic and anterior cingulate subregions, contribute a pup-specific bias to the motivational circuitry. As the postpartum period progresses and the pups grow older, it is further revealed that maternal responsiveness becomes progressively less dependent on the medial preoptic area and medial prefrontal cortex infralimbic activity, and more distributed in the maternal circuitry, such that additional network components, including the medial prefrontal cortex prelimbic subregion, are recruited with maternal experience, and contribute to the expression of late postpartum maternal behaviour. Collectively, our findings provide strong evidence that the remarkable ability of postpartum females to successfully care for their developing infants is subserved by a distributed neural network that carries out efficient and dynamic processing of complex, constantly changing incoming environmental and pup-related stimuli, ultimately allowing the progression of appropriate expression and waning of maternal responsiveness across the postpartum period.

M1291 Visual Motion Induced Nausea Alters Functional Brain Connectivity - An FMRI Study

identify amygdalo-centric networks operating during rectal distension (seed PLS). Structural equation modeling (SEM) was used to characterize and test for differences in effective connectivity of an amygdala-based emotional arousal network identified in the seed PLS. Results: Task PLS identified a distension-related network (72% of total variance, p<.001) engaged to a greater extent in patients relative to HC. The network included homeostatic afferent regions (thalamus, bilateral anterior insula (aINS), anterior cingulate subregions), limbic/paralimbic regions (right amygdala (Amyg), parahippocampal gyrus, hippocampus, infragenual and posterior cingulate regions), visceral/somatic sensory regions and bilateral orbital/medial prefrontal cortices (omPFC). Subsequent seed PLS identified a network of regions (24%, p<.001) correlated differently with right Amyg in IBS patients relative to HC. This network was characterized bymore positive connectivity with bilateral anterior cingulate, omPFC and right aINS and more negative connectivity with bilateral posterior cingulate cortex, sensory and motor cortices in patients relative to HC. Effective connectivity analysis demonstrated a lack of inhibitory influence of omPFC on Amyg and alterations in connectivity within the emotional arousal circuit in patients relative to HC. Conclusions: In female subjects: 1. Relative to sham inflation, an acute pelvic visceral stimulus engages a network characterized by increased activity in homeostatic afferent network regions and decreased activity in limbic and paralimbic regions. This network is more engaged in patients compared to HCs. 2. Patients show alterations in functional and effective connectivity of regions within an emotional-arousal network consistent with less effective inhibitory corticolimbic modulation during aversive rectal distension. Supported by NIH grants: K08 DK071626, NR04881, P50 DK64539, R24 AT002681, DK48351

Sensitizing regimens of (±)3, 4-methylenedioxymethamphetamine (ecstasy) elicit enduring and differential structural alterations in the brain motive circuit of the rat

Repeated, intermittent exposure to the psychomotor stimulants amphetamine and cocaine induces a progressive and enduring augmentation of their locomotor-activating effects, known as behavioral sensitization, which is accompanied by similarly stable adaptations in the dendritic structure of cortico-striatal neurons. We examined whether repeated exposure to the increasingly abused amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) also results in long-lasting behavioral and morphological changes in mesocortical (medial prefrontal cortex) and ventral striatal (nucleus accumbens) neurons. Rats received two daily injections of either 5.0 mg/kg (±)-MDMA or saline vehicle, ∼6 h apart, for 3 consecutive days, followed by 4 drug-free days for a total of 3 weeks. Following a 4-week drug-free period, MDMA-pretreated rats displayed behavioral sensitization, as well as large increases in spine density and the number of multiple-headed spines on medium spiny neurons in core and shell subregions of nucleus accumbens. In medial prefrontal cortex, the prelimbic subregion showed increased spine density on distal dendrites of layer V pyramidal neurons, while the anterior cingulate subregion showed a change in the distribution of dendritic material instead. Collectively, our results show that long-lasting locomotor sensitization to MDMA is accompanied by reorganization of synaptic connectivity in limbic-cortico-striatal circuitry. The differential plasticity in cortical subregions, moreover, suggests that drug-induced structural changes are not homogeneous and may be specific to the circuitry underlying long-term changes in drug-seeking and drug-taking behavior.

Induction of early growth response gene 2 expression in the forebrain of mice performing an attention-set-shifting task

Early growth response (egr) genes encode transcription factors that are induced by stimuli that cause synaptic plasticity. Here we show that the expression of one member of this family, egr-2, is induced in the orbital frontal cortex (OFC) and medial prefrontal cortex (mPFC) of mice performing an attention-set-shifting task (ASST). The ASST is a series of two-choice perceptual discriminations between different odors and textures. Within the OFC and mPFC, different subregions exhibited egr-2 induction in response to different test-related features. In the medial OFC and the anterior cingulate subregion of the mPFC, egr-2 induction occurred in response to exposure to the novel odor stimulus. In the ventrolateral OFC and the pre- and infralimbic mPFC, additional egr-2 induction occurred during the associative learning phase of the ASST. In the infralimbic mPFC, further egr-2 induction occurred when mice performed set-shifting and reversal learning phases of the ASST. Mice with enhanced set-shifting performance exhibited decreased egr-2 induction in the mPFC indicating that the magnitude of egr-2 induction correlates with the magnitude of attentional demand. This decrease was largest in the infralimbic mPFC suggesting further that egr-2 induction in this region plays a role in the attentional control during set-shifting.In contrast to egr-2, neither egr-1 nor egr-3 expression was altered in ASST-tested mice, and no egr-2 induction occurred in mice that performed a spatial working memory task. These findings suggest a specific role of egr-2-mediated transcriptional activation in cognitive functions associated with attention.

Erratum

Bipolar DisordersVolume 8, Issue 5p1 p. 522-522 Free Access Erratum This article corrects the following: Anterior cingulate subregion volumes and executive function in bipolar disorder Molly E Zimmerman, Melissa P DelBello, Glen E Getz, Paula K Shear, Stephen M Strakowski, Volume 8Issue 3Bipolar Disorders pages: 281-288 First Published online: May 12, 2006 First published: 16 October 2006 https://doi.org/10.1111/j.1399-5618.2006.00410.xCitations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat In (1), the following error was published on page 285: Table 2, aData are given in cubic centimeters. The text is incorrect and should have read: Table 2, aData are given in cubic millimeters. We apologize for this error. Reference 1 Zimmerman ME, DelBello MP, Getz GE, Shear PK, Strakowski SM. Anterior cingulate subregion volumes and executive function in bipolar disorder. Bipolar Disord 2006; 8: 281– 288. Wiley Online LibraryPubMedWeb of Science®Google Scholar Citing Literature Volume8, Issue5p1October 2006Pages 522-522 ReferencesRelatedInformation

Anterior cingulate subregion volumes and executive function in bipolar disorder

Although research findings suggest a relationship between the function of anterior cingulate cortex (ACC) and both cognitive ability and the pathophysiology of bipolar disorder (BPD), few studies have examined cognitive correlates of specific ACC subregion volumes in BPD. Therefore, the primary aim of this study was to examine the relationship between magnetic resonance imaging (MRI)-derived gray and white matter volumes of ACC subregions (caudal, rostral, and subgenual) and performance on tests of executive function in 27 patients with BPD and 22 healthy subjects. 1.5T MRI and neuropsychological assessment were conducted with all participants. MANCOVA revealed statistically significant group differences in performance on executive function measures. However, no group differences were observed in any of the ACC white matter or gray matter regions of interest. Multiple regression analyses revealed that rostral and subgenual gray matter each interacted significantly with group in predicting performance on the Wisconsin Card Sorting Test. In addition, a significant interaction was observed between group and both rostral gray and white matter in predicting performance on the Trail Making Test. The results of this preliminary study support the extant literature that suggests that patients with BPD perform more poorly than healthy subjects on tests of executive function. Furthermore, the relationship between ACC subregion volumes and cognitive test performance was found to differ between patients with BPD and healthy subjects, despite comparable ACC volumes in the two groups.

Potential contributions of efferents from medial prefrontal cortex to neural activation following sexual behavior in the male rat

The limbic system plays an important role in the regulation of sexual motivation and reward. At the core of this system is an interconnected mesocorticolimbic circuit, comprised of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex. Previously, our laboratory showed that sexual behavior causes neural activation in the ventral tegmental area of male rats. The main goal of this study is to identify afferent inputs to ventral tegmental area neurons that may contribute to their activation during sexual behavior. Hence, the anterograde tracer biotinylated dextran amine was injected into subregions of the rat medial prefrontal cortex, which is known to project to the ventral tegmental area. Visualization of biotinylated dextran amine-labeled axons was combined with immunostaining for sex-induced Fos expression. Quantitative analysis showed that the majority of sex-activated ventral tegmental area neurons receive putative contacts from the infralimbic and prelimbic—but not the anterior cingulate—subregions of the medial prefrontal cortex. Thus, inputs from infralimbic area and prelimbic are in an anatomical position to provide a major source of input during sexual behavior. A second goal of this study was to determine if the medial prefrontal cortex projects to sex-activated neurons in other brain regions important for sexual behavior and motivation. Infralimbic area and prelimbic area sent projections to nucleus accumbens, medial preoptic area, principal nucleus of the bed nucleus of the stria terminalis, basolateral amygdala, and parvocellular subparafasicular thalamic nucleus. Thus, the infralimbic and prelimbic subregions of the medial prefrontal cortex may also influence sexual behavior and motivation via brain regions other than the ventral tegmental area.

Selective Antagonism at Dopamine D3 Receptors Enhances Monoaminergic and Cholinergic Neurotransmission in the Rat Anterior Cingulate Cortex

Recent neuroanatomical and functional investigations focusing on dopamine (DA) D(3) receptors have suggested a potential role of this receptor in psychiatric diseases such as schizophrenia and drug dependence. In line with the key role of the prefrontal cortex in psychiatric disorders, the present study aimed at assessing the effects of the acute systemic administration of the selective DA D(3) receptor antagonist SB-277011-A on the in vivo extracellular levels of monoamines (DA, norepinephrine (NE), and serotonin (5-HT)) and acetylcholine (ACh) in the anterior cingulate subregion of the medial prefrontal cortex. The in vivo neurochemical profile of SB-277011-A (10 mg/kg, i.p.) in the anterior cingulate cortex was compared with both typical and atypical antipsychotics including clozapine (10 mg/kg, s.c.), olanzapine (10 mg/kg, s.c.), sulpiride (10 mg/kg, s.c.), and haloperidol (0.5 mg/kg, s.c.). The acute administration of SB-277011-A, clozapine, and olanzapine produced a significant increase in extracellular levels of DA, NE, and ACh without affecting levels of 5-HT. Sulpiride also significantly increased extracellular DA, but with a delayed onset over SB-277011-A, clozapine, and olanzapine. In contrast, haloperidol failed to alter any of the three monoamines and ACh in the anterior cingulate cortex. These findings add to a growing body of evidence suggesting a differentiation between typical and atypical antipsychotic drugs (APDs) in the anterior cingulate cortex and a role of DA D(3) receptors in desired antipsychotic drug profile. Similar to their effects on DA and NE, SB-277011-A, clozapine, and olanzapine increased extracellular levels of ACh, whereas haloperidol and sulpiride did not alter ACh. The results obtained in the present study provide evidence of the important role of DA D(3) receptors in the effect of pharmacotherapeutic agents that are used for the treatment of psychiatric disorders such as schizophrenia and drug dependence.

Mice Lacking Dopamine D2and D3Receptors Have Spatial Working Memory Deficits

Mice deficient for dopamine D(2) and D(3) receptors exhibit blunted c-fos responses to D(1) agonist stimulation. Stereologic cell counting revealed decreased numbers of medial prefrontal cortex neurons that express Fos immunoreactivity in all layers, particularly in the prelimbic and anterior cingulate subregions. Pretreatment of these mutants with a single, low dose of methamphetamine (METH) led to a sustained increase in the number of neurons that express Fos immunoreactivity in response to a D(1) agonist challenge, which was most significant in prelimbic and anterior cingulate subregions. The increased c-fos responses reached wild-type-like levels in METH-pretreated D(2) mutants but remained submaximal in METH-pretreated D(3) mutants. Additional studies tested the performance of wild type and mutants in a delayed alternation test, a cognitive task critically dependent on optimal activation of prefrontal cortical D(1) receptors by synaptically released dopamine. Both D(2) and D(3) mutants exhibited deficits in their spatial working memory, with increasing impairments at increasing delays. Whereas METH pretreatment rescued the spatial working memory of D(2) mutants, it had no effect on D(3) mutants. These data suggest that the sustained improvement of spatial working memory in METH-pretreated D(2) mutants is attributable to D(1) receptor-mediated mechanisms.

Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits.

Mice deficient for dopamine D(2) and D(3) receptors exhibit blunted c-fos responses to D(1) agonist stimulation. Stereologic cell counting revealed decreased numbers of medial prefrontal cortex neurons that express Fos immunoreactivity in all layers, particularly in the prelimbic and anterior cingulate subregions. Pretreatment of these mutants with a single, low dose of methamphetamine (METH) led to a sustained increase in the number of neurons that express Fos immunoreactivity in response to a D(1) agonist challenge, which was most significant in prelimbic and anterior cingulate subregions. The increased c-fos responses reached wild-type-like levels in METH-pretreated D(2) mutants but remained submaximal in METH-pretreated D(3) mutants. Additional studies tested the performance of wild type and mutants in a delayed alternation test, a cognitive task critically dependent on optimal activation of prefrontal cortical D(1) receptors by synaptically released dopamine. Both D(2) and D(3) mutants exhibited deficits in their spatial working memory, with increasing impairments at increasing delays. Whereas METH pretreatment rescued the spatial working memory of D(2) mutants, it had no effect on D(3) mutants. These data suggest that the sustained improvement of spatial working memory in METH-pretreated D(2) mutants is attributable to D(1) receptor-mediated mechanisms.