Neurabin in the anterior cingulate cortex regulates anxiety-like behavior in adult mice
- Susan S Kim†1,
- Hansen Wang†1,
- Xiang-Yao Li†1,
- Tao Chen†1,
- Valentina Mercaldo1,
- Giannina Descalzi1,
- Long-Jun Wu1 and
- Min Zhuo1, 2Email author
© Kim et al; licensee BioMed Central Ltd. 2011
Received: 20 December 2010
Accepted: 19 January 2011
Published: 19 January 2011
Affective disorders, which include anxiety and depression, are highly prevalent and have overwhelming emotional and physical symptoms. Despite human brain imaging studies, which have implicated the prefrontal cortex including the anterior cingulate cortex (ACC), little is known about the ACC in anxiety disorders. Here we show that the ACC does modulate anxiety-like behavior in adult mice, and have identified a protein that is critical for this modulation. Absence of neurabin, a cytoskeletal protein, resulted in reduced anxiety-like behavior and increased depression-like behavior. Selective inhibition of neurabin in the ACC reproduced the anxiety but not the depression phenotype. Furthermore, loss of neurabin increased the presynaptic release of glutamate and cingulate neuronal excitability. These findings reveal novel roles of the ACC in anxiety disorders, and provide a new therapeutic target for the treatment of anxiety disorders.
Affective disorders are among the most common psychiatric diagnoses . Selective Serotonin Reuptake Inhibitors (SSRIs) are the most commonly prescribed drugs for such mood disorders, but very little is known regarding the molecular mechanisms and the specific neural circuits that underlie both the disorders and the drugs' effects . Additionally, while treatments for affective disorders are effective, many patients are left with residual symptoms or experience side effects that limit their adherence to prescribed regimens . Although numerous human brain imaging studies have implicated the prefrontal cortex (PFC) including the ACC in affective disorders [4–6], the exact role of the ACC in affective disorders still remains unknown.
Neurabin is a cytoskeletal protein found both in dendritic spines and axon terminals . Neurabin interacts directly with the filamentous actin cytoskeleton [8, 9]. In addition to the actin-binding domain, neurabin contains several other domains critical for their function, such as protein phosphatase 1(PP1)-binding motif [10, 11]. Previous studies in the hippocampus have found that neurabin contributes to the regulation of glutamate AMPA receptor functions and its related plasticity . Additionally, numerous drugs affecting anxiety affect AMPA receptor-mediated excitatory transmission in the PFC , and antagonism of AMPA receptors have been found to reduce anxiety-like behaviors [14, 15]. Studies have also found that synaptic transmission and plasticity in the ACC is critical for pain, fear, and learning and memory [16–24], and recently, it was found that neurons in the ACC form local excitatory and inhibitory connections . In the ACC, excitatory synaptic transmission is mediated by glutamate and GABA mediates inhibitory synaptic transmission. As benzodiazepines, which are clinically used to treat anxiety disorders, promote binding of GABA to GABAA receptor, these connections in the ACC could be essential in modulating anxiety-like behaviors.
Here, we demonstrate that the injections of muscimol, a potent, selective GABAA receptor agonist, as well as midazolam, a clinically used benzodiazepine, into the ACC reduced anxiety-like behaviors. Neurabin knockout (KO) mice had reduced anxiety-like behavior but increased depression-like behavior. Selective inhibition of neurabin in the ACC using siRNA reproduced the anxiety-like behavior phenotype but did not affect the depression-like behavior. Furthermore, deletion or reduction of neurabin increased the presynaptic release of glutamate and cingulate neuronal excitability. This study demonstrates the role of the ACC in affective disorders, and that neurabin may be a possible new therapeutic target for the treatment of anxiety disorders.
Materials and methods
Adult male mice (8-12 weeks old) were used for all experiments. All mice were maintained on a 12 h light/dark cycle with food and water provided ad libitum. All protocols used were approved by The Animal Care and Use Committee at the University of Toronto.
Elevated plus maze
The apparatus consisted of two opposing open and closed arms. For each test, the animal was placed in the centre square and allowed to move freely for 5 min. The number of entries and time spent in each arm were recorded.
To record horizontal activity, Activity Monitor system from Med Associates (St. Albans, VT) was used. Briefly, this system used paired sets of photo beams to detect movement in the open field and movement was recorded as beam breaks. The open field was placed inside an isolation chamber with dim illumination and a fan. Each subject was placed in the centre of the open field and activity was measured for 30 minutes.
The apparatus consisted of a rectangular Plexiglas box (44 × 8.5 × 25 cm) equally divided into a light and dark compartment that was separated by a door. Each animal was placed in the light compartment and was allowed 10 sec to explore, after which the door to the dark compartment was opened. The time spent in both compartments was recorded for 10 min.
Elevated emergence task
The apparatus consisted of a rectangular Plexiglas floor equally divided into opaque and clear sections, with the opaque section surrounded on three sides by high walls, resting on an elevated platform, while clear section was not enclosed and suspended over the floor from the elevated platform. For each test, the animal was placed in the opaque section and was allowed to move freely for 5 min. The latency to cross into the clear floor and time spent were recorded.
Forced swim test
Mice were placed in a transparent plastic tub containing water (23-25°C). Each mouse was tested for 6 minutes. The mouse was allowed to swim freely for 2 min. Time spent immobile (aside from small maintenance movements) was recorded during the last 4 minutes. After the test, the animals were allowed to dry in a heated cage before being returned to the home cage. The water was changed after each mouse.
Briefly, cultured cortical neurons were harvested and homogenized in lysis buffer. Electrophoresis of equal amounts of total protein was run on SDS-polyacrylamide gels. Separated proteins were transferred to polyvinylidene fluoride membranes overnight at 4°C. Membranes were probed with primary antibodies against neurabin (Millipore Corporation, California) and actin (Sigma, MO) overnight at 4°C. The membranes were then incubated with horseradish peroxidase-coupled secondary antibody for 2 h at room temperature followed by enhanced chemiluminescence (ECL) detection using Western Lightning Chemiluminescence Reagent Plus (Perkin Elmer Life sciences, MA). The density of immunoblots was measured with NIH ImageJ software.
Brain cannulation and microinjection
Mice were anesthetized with i.p. injection of a mixture of xylazine (10 mg/kg) and ketamine (130 mg/kg). The fur above the skull was shaved and the skin cleaned with alcohol, Triadine, then alcohol. The head of the mouse was placed in a stereotaxic device and lubricant applied to the eyes. An incision was made over the skull and the surface exposed. A 24 gauge guide cannula was implanted bilaterally into the ACC. Dental cement was used to keep the cannula in place and sterile silk sutures were used to close the skin. Mice were injected with 1.0 ml sterile saline (i.p.) for hydration. Animals were allowed to recover in a chamber containing a recirculating water blanket until their righting reflex returned; they were then placed in a clean cage and given moistened food. Ketoprofen (0.5 mg/ml) was given intraoperatively as an analgesic. The animal was given at least one week to fully recover. For microinjection, a 30 gauge injection cannula, which is 0.8 mm lower than the guide, were used for drug infusion, 0.5 ul delivered over 90 sec. Behavioral responses were measured 20 min after microinjection.
Primary cortical neuron culture
Cortical neurons were prepared from postnatal day 0 (P0) mice using methods as described previously [26, 27]. The cortices were dissected, minced, and trypsinized for 15 min using 0.125% trypsin (Invitrogen, CA). Cultures were grown in Neurobasal-A medium supplemented with B27 and 2 mM GlutaMax (Invitrogen, CA) and incubated at 37°C in 95% air, 5% CO2 with 95% humidity. Cultures were transfected with neurabin or control siRNA using Transfection reagent for siRNA (Invitrogen, CA) at DIV 10. The expression of neurabin was detected 40 hours later by Western blot.
Coronal brain slices (300 μm) containing the ACC from six- to eight-week-old male mice were prepared using standard methods . Slices were transferred to a submerged recovery chamber with oxygenated (95% O2and 5% CO2) artificial cerebrospinal fluid (ACSF) containing (in mM): 124 NaCl, 2.5 KCl, 2 CaCl2, 2 MgSO4, 25 NaHCO3, 1 NaH2PO4, 10 glucose at room temperature for at least 1 hour.
All electrophysiological experiments were performed at room temperature. An Olympus BX51WI microscope (Tokyo, Japan) with infrared DIC optics was used for visualization of whole-cell patch clamp recording. Excitatory postsynaptic currents (EPSCs) were recorded from layer II/III neurons with an Axon 200 B amplifier (Molecular devices, CA) and the stimulations were delivered by a bipolar tungsten stimulating electrode placed in layer V of the ACC slices. EPSCs were induced by repetitive stimulations (duration is 200 μs, intensity is adjusted to induce EPSCs with amplitude of 50-100 pA at 0.05 Hz and neurons were voltage clamped at -70 mV. The recording pipettes (3-5 MΩ) were filled with solution containing (mM): 120 K-gluconate, 5 NaCl, 1 MgCl2, 0.2 EGTA, 10 HEPES, 2 Mg-ATP, 0.1 Na3-GTP and 10 phosphocreatine disodium salt (adjusted to pH 7.2 with KOH). Picrotoxin (100 μM) was always present to block GABAAreceptor-mediated inhibitory currents and monitored throughout the synaptic currents. In the mEPSC and mIPSC experiments, 1 μM TTX were perfused into the ACSF to blocking the activities of sodium currents. Access resistance was 15-30 MΩ and was monitored throughout the experiment. Data were discarded if access resistance changed more than 15% during an experiment.
siRNA preparation and microinjection
Stealth neurabin-targeted siRNA or siRNA negative control (Invitrogen, CA) and Invivofectamine Reagent (Invitrogen, CA) were gently mixed together then incubated for 30 min at room temperature in an orbital shaker. 5% glucose was added, and the mixture was transferred into an Amicon Ultra-4 Centrifugal Filter Device (Ultracel - 100 k; Millipore, MA) and centrifuged for 1 hour.
Mice were anesthetized with i.p. injection of a mixture of xylazine (10 mg/kg) and ketamine (130 mg/kg). A 30 gauge needle was lowered into the ACC (AP 0.7 mm; ML 0.3 mm; VD 1.75 mm) and the prepared siRNA was injected. Mice were injected with 1.0 ml sterile saline (i.p.) for hydration. Ketoprofen (0.5 mg/ml) was given intraoperatively as an analgesic.
Statistical comparisons were made using the Student's t-test or two way ANOVA to identify significant differences. All data are expressed as mean value ± standard error of the mean. In all cases, p < 0.05 was considered statistically significant.
The ACC is critical for anxiety- and depression-like behaviors
Neurabin modulates anxiety-like behavior of the elevated plus maze
Injecting neurabin siRNA into the ACC reduced anxiety-like behavior
Deletion of neurabin increased the presynaptic transmitter release and neuronal excitability in the ACC
Numerous human brain imaging studies have implicated the ACC, an area long known to be engaged in both cognitive and emotional processing [34, 35], in affective disorders [4–6]. However, lesion studies have not reflected the brain imaging data . Additionally, few animal studies have examined the role of the ACC in affective disorders, and similar to the human studies, produced conflicting results . Therefore, the exact role of the ACC in affective disorders still remains to be determined.
The present findings are the first, to our knowledge, to show the importance of neurabin in anxiety- and depression-related behaviors. We found that neurabin KO mice showed reduced anxiety-like behaviors in the elevated plus maze. However, when tested on two other conflict paradigms, the open field and the light/dark test, the results remained comparable between genotypes, suggesting that neurabin selectively modulates the anxiety-like behaviors of the elevated plus maze. Next, neurabin-targeted siRNA was injected into the ACC to see if anxiety-like behavior would still be affected without the complete absence of neurabin. Two to three days following injection, the mice were tested on the elevated plus maze, and similarly to neurabin KO mice, also had reduction in anxiety-like behavior, indicating that reducing the level of neurabin in the ACC was sufficient enough for the modulation of anxiety-like behaviors.
As anxiety and depression are often comorbid, forced swim test was used to assess the depression-related behavior of neurabin KO mice. Compared to the WT, neurabin KO mice had increased immobility, suggesting that neurabin KO mice have increased behavioral despair. The result is somewhat surprising, as anxiety and depression have been suggested to share similar genetic vulnerabilities [38, 39] and neuropharmacology, supported by findings that SSRIs are effective treatments for both depression and a number of anxiety disorders . That neurabin appears to act in opposing fashion in anxiety- and depression-related behaviors does not negate this theory, as neurabin is critical for the modulation of both, since the absence of neurabin alters the anxiety- and depression-related behaviors. However, neurabin clearly affects both behaviors in different ways, possibly through different neurocircuitries that are specific for anxiety or depression. Interestingly, when neurabin-targeted siRNA was injected into the ACC, there were no significant differences in depression-like behavior between groups, suggesting that neurabin in the ACC may not be required to modulate depression-related behaviors. However, anxiety-related behavior was still reduced by a partial loss of neurabin. This lends support to the idea that neurabin modulates anxiety and depression, but through different neurocircuitries that is specific for one behavior or other. It may also be possible that the reduction in PP1 levels observed by Allen et al.  in neurabin KO mice could be absent in mice injected with neurabin-targeted siRNA, and that it may be PP1 activity which is critical for depression-like behavior.
We have also shown that the ACC is indeed critical for anxiety- and depression-like behaviors in mice. Using microinjections of muscimol, a potent, selective GABAA receptor agonist, we found that in adult mice, the ACC is critical for anxiety-like behaviors. Mice that had been given microinjections of muscimol into the ACC had reduced anxiety-like behaviors when compared to the mice injected with saline. As well, microinjections of midazolam, a short-acting benzodiazepine, produced similar results, indicating that application of a clinically used anxiolytic into the ACC was sufficient enough to reduce anxiety-like behavior. Additionally, muscimol-injected mice also had reduced depression-like behavior on the forced swim test. However, the closed arm entries and total arm entries remained comparable to controls, suggesting that the phenotypic differences weren't due to hyperactivity. The data, therefore, suggest that the ACC is critical for anxiety- and depression-like behaviors. The work by Bissiere et al. , which found that the rostral ACC does not appear to modulate the anxiety-related behavior of rats, doesn't necessarily contradict this current study. As noted by the authors, the area lesioned had selective ipsilateral projections to and from the basolateral amygdala, which previous studies have shown isn't required for the elevated plus maze [41, 42]. Additionally, the data from Bissiere et al. show relatively high baseline anxiety, indicating that a possible floor effect may mask potential anxiogenic effects in the elevated plus maze . Furthermore, lesions affect neurons, passing nerve fibers and local glial cells in a non-selective manner, which could have affected the findings.
Our data suggests that neurabin in the ACC is critical for the modulation of the anxiety-like behavior (particularly with respect to elevation) but not depression-like behavior. However, we cannot discount the fact that the elevated plus maze and the elevated emergence task also contain aversive open spaces, even more so than the open field, which is enclosed in a sound-attenuating chamber. Additional tests will need to be devised and conducted to test solely for elevation, and to further determine the downstream effectors of neurabin and their role in affective disorders. In sum, our findings of the requirement of neurabin in anxiety-like behaviors provide a potential novel molecular target for designing new drug treatments for anxiety disorders.
This work was supported by grants from the EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health, Canada Research Chair, NeuroCanada, and CIHR operating grants (CIHR66975 and CIHR84256) (MZ). MZ is also supported by the World-Class University (WCU) program of the Ministry of Education, Science and Technology in Korea through KOSEF (R32-10142). HW, X-YL, TC & L-JW are supported by postdoctoral fellowships from CIHR and Fragile X Research Foundation of Canada. We would also like to thank Dr. Paul Greengard for providing neurabin KO and WT mice.
- Hohoff C: Anxiety in mice and men: a comparison. J Neural Transm. 2009, 116: 679-687. 10.1007/s00702-009-0215-z.View ArticlePubMedGoogle Scholar
- Lledo PM: Dissecting the pathophysiology of depression with a Swiss army knife. Neuron. 2009, 62: 453-455. 10.1016/j.neuron.2009.05.004.View ArticlePubMedGoogle Scholar
- Gorman JM, Kent JM, Coplan JD: Current and emerging therapeutics of anxiety and stress disorders. Neuropsychopharmacology: The Fifth Generation of Progress. Edited by: Davis KL, Charney DS, Coyle JT, Nemeroff C. 2002, Philadelphia: Lippincott Williams and Wilkins, 967-80.Google Scholar
- Brody AL, Saxena S, Mandelkern MA, Fairbanks LA, Ho ML, Baxter LR: Brain metabolic changes associated with symptom factor improvement in major depressive disorder. Biol Psychiatry. 2001, 50: 171-178. 10.1016/S0006-3223(01)01117-9.View ArticlePubMedGoogle Scholar
- Damsa C, Kosel M, Moussally J: Current status of brain imaging in anxiety disorders. Curr Opin Psychiatry. 2009, 22: 96-110. 10.1097/YCO.0b013e328319bd10.View ArticlePubMedGoogle Scholar
- Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA: Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000, 48: 830-843. 10.1016/S0006-3223(00)01036-2.View ArticlePubMedGoogle Scholar
- Muly EC, Allen P, Mazloom M, Aranbayeva Z, Greenfield AT, Greengard P: Subcellular distribution of neurabin immunolabeling in primate prefrontal cortex: comparison with spinophilin. Cereb Cortex. 2004, 14: 1398-1407. 10.1093/cercor/bhh101.View ArticlePubMedGoogle Scholar
- Nakanishi H, Obaishi H, Satoh A, Wada M, Mandai K, Satoh K, Nishioka H, Matsuura Y, Mizoguchi A, Takai Y: Neurabin: a novel neural tissue-specific actin filament-binding protein involved in neurite formation. J Cell Biol. 1997, 139: 951-961. 10.1083/jcb.139.4.951.PubMed CentralView ArticlePubMedGoogle Scholar
- Satoh A, Nakanishi H, Obaishi H, Wada M, Takahashi K, Satoh K, Hirao K, Nishioka H, Hata Y, Mizoguchi A, Takai Y: Neurabin-II/spinophilin. An actin filament-binding protein with one pdz domain localized at cadherin-based cell-cell adhesion sites. J Biol Chem. 1998, 273: 3470-3475. 10.1074/jbc.273.6.3470.View ArticlePubMedGoogle Scholar
- Allen PB, Zachariou V, Svenningsson P, Lepore AC, Centonze D, Costa C, Rossi S, Bender G, Chen G, Feng J, et al: Distinct roles for spinophilin and neurabin in dopamine-mediated plasticity. Neuroscience. 2006, 140: 897-911. 10.1016/j.neuroscience.2006.02.067.View ArticlePubMedGoogle Scholar
- Sarrouilhe D, di Tommaso A, Metaye T, Ladeveze V: Spinophilin: from partners to functions. Biochimie. 2006, 88: 1099-1113. 10.1016/j.biochi.2006.04.010.View ArticlePubMedGoogle Scholar
- Wu L, Ren M, Wang H, Kim S, Cao X, Zhuo M: Neurabin Contributes to Hippocampal Long-Term Potentiation and Contextual Fear Memory. Plos One. 2008, 3: 1-View ArticleGoogle Scholar
- Weisstaub N, Zhou M, Lira A, Lambe E, Gonzalez-Maeso J, Hornung J, Sibille E, Underwood M, Itohara S, Dauer W, et al: Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science. 2006, 536-540. 10.1126/science.1123432.Google Scholar
- Kapus GL, Gacsalyi I, Vegh M, Kompagne H, Hegedus E, Leveleki C, Harsing LG, Barkoczy J, Bilkei-Gorzo A, Levay G: Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents: effects of GYKI 52466 and its novel analogues. Psychopharmacology (Berl). 2008, 198: 231-241. 10.1007/s00213-008-1121-z.View ArticleGoogle Scholar
- Bergink V, van Megen HJ, Westenberg HG: Glutamate and anxiety. Eur Neuropsychopharmacol. 2004, 14: 175-183. 10.1016/S0924-977X(03)00100-7.View ArticlePubMedGoogle Scholar
- Leknes S, Tracey I: A common neurobiology for pain and pleasure. Nat Rev Neurosci. 2008, 9: 314-320. 10.1038/nrn2333.View ArticlePubMedGoogle Scholar
- Frankland PW, Bontempi B, Talton LE, Kaczmarek L, Silva AJ: The involvement of the anterior cingulate cortex in remote contextual fear memory. Science. 2004, 304: 881-883. 10.1126/science.1094804.View ArticlePubMedGoogle Scholar
- Maviel T, Durkin TP, Menzaghi F, Bontempi B: Sites of neocortical reorganization critical for remote spatial memory. Science. 2004, 305: 96-99. 10.1126/science.1098180.View ArticlePubMedGoogle Scholar
- Devinsky O, Morrell MJ, Vogt BA: Contributions of anterior cingulate cortex to behaviour. Brain. 1995, 118 (1): 279-306. 10.1093/brain/118.1.279.View ArticlePubMedGoogle Scholar
- Zhuo M: A synaptic model for pain: long-term potentiation in the anterior cingulate cortex. Mol Cells. 2007, 23: 259-271.PubMedGoogle Scholar
- Zhuo M: Plasticity of NMDA receptor NR2B subunit in memory and chronic pain. Mol Brain. 2009, 2: 4-10.1186/1756-6606-2-4.PubMed CentralView ArticlePubMedGoogle Scholar
- Wu LJ, Toyoda H, Zhao MG, Lee YS, Tang J, Ko SW, Jia YH, Shum FW, Zerbinatti CV, Bu G, et al: Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation. J Neurosci. 2005, 25: 11107-11116. 10.1523/JNEUROSCI.1678-05.2005.View ArticlePubMedGoogle Scholar
- Wei F, Li P, Zhuo M: Loss of synaptic depression in mammalian anterior cingulate cortex after amputation. J Neurosci. 1999, 19: 9346-9354.PubMedGoogle Scholar
- Wei F, Zhuo M: Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat. J Physiol. 2001, 532: 823-833. 10.1111/j.1469-7793.2001.0823e.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Wu LJ, Li X, Chen T, Ren M, Zhuo M: Characterization of intracortical synaptic connections in the mouse anterior cingulate cortex using dual patch clamp recording. Mol Brain. 2009, 2: 32-10.1186/1756-6606-2-32.PubMed CentralView ArticlePubMedGoogle Scholar
- Wang H, Gong B, Vadakkan KI, Toyoda H, Kaang BK, Zhuo M: Genetic evidence for adenylyl cyclase 1 as a target for preventing neuronal excitotoxicity mediated by N-methyl-D-aspartate receptors. J Biol Chem. 2007, 282: 1507-1517. 10.1074/jbc.M607291200.View ArticlePubMedGoogle Scholar
- Wang H, Wu LJ, Kim SS, Lee FJ, Gong B, Toyoda H, Ren M, Shang YZ, Xu H, Liu F, et al: FMRP acts as a key messenger for dopamine modulation in the forebrain. Neuron. 2008, 59: 634-647. 10.1016/j.neuron.2008.06.027.View ArticlePubMedGoogle Scholar
- Porsolt RD, Anton G, Blavet N, Jalfre M: Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol. 1978, 47: 379-391. 10.1016/0014-2999(78)90118-8.View ArticlePubMedGoogle Scholar
- Steru L, Chermat R, Thierry B, Simon P: The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl). 1985, 85: 367-370. 10.1007/BF00428203.View ArticleGoogle Scholar
- Bai F, Li X, Clay M, Lindstrom T, Skolnick P: Intra- and interstrain differences in models of "behavioral despair". Pharmacol Biochem Behav. 2001, 70: 187-192. 10.1016/S0091-3057(01)00599-8.View ArticlePubMedGoogle Scholar
- Finn DA, Rutledge-Gorman MT, Crabbe JC: Genetic animal models of anxiety. Neurogenetics. 2003, 4: 109-135.PubMedGoogle Scholar
- Fox MW: The visual cliff test for the study of visual depth perception in the mouse. 1965Google Scholar
- Crawley JN: What's wrong with my mouse?: behavioral phenotyping of transgenic and knockout mice. 2000, New York: Wiley-LissGoogle Scholar
- Drevets WC, Raichle ME: Reciprocal suppression of regional cerebral blood flow during emotional versus higher cognitive processes: Implications for interactions between emotion and cognition. Cognition and Emotion. 1998, 12: 353-385. 10.1080/026999398379646.View ArticleGoogle Scholar
- Vogt BA, Vogt LJ, Nimchimsky EA, Hof PR: Primate cingulate cortex chemoarchitecture and its disruption in Alzheimer's disease. Handbook of Chemical Neuroanatomy, the Primate Nervous System. Edited by: Bloom FE, Bjorklund A, Hokfelt T. 1997, Amsterdam: Elsevier, 13: 455-528.Google Scholar
- Luu P, Posner MI: Anterior cingulate cortex regulation of sympathetic activity. Brain. 2003, 126: 2119-2120. 10.1093/brain/awg257.View ArticlePubMedGoogle Scholar
- Bissiere S, McAllister KH, Olpe HR, Cryan JF: The rostral anterior cingulate cortex modulates depression but not anxiety-related behaviour in the rat. Behav Brain Res. 2006, 175: 195-199. 10.1016/j.bbr.2006.08.022.View ArticlePubMedGoogle Scholar
- Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ: Major depression and generalized anxiety disorder. Same genes, (partly) different environments?. Arch Gen Psychiatry. 1992, 49: 716-722.View ArticlePubMedGoogle Scholar
- Roy MA, Neale MC, Pedersen NL, Mathe AA, Kendler KS: A twin study of generalized anxiety disorder and major depression. Psychol Med. 1995, 25: 1037-1049. 10.1017/S0033291700037533.View ArticlePubMedGoogle Scholar
- Leonardo ED, Hen R: Genetics of affective and anxiety disorders. Annu Rev Psychol. 2006, 57: 117-137. 10.1146/annurev.psych.57.102904.190118.View ArticlePubMedGoogle Scholar
- Decker MW, Curzon P, Brioni JD: Influence of separate and combined septal and amygdala lesions on memory, acoustic startle, anxiety, and locomotor activity in rats. Neurobiol Learn Mem. 1995, 64: 156-168. 10.1006/nlme.1995.1055.View ArticlePubMedGoogle Scholar
- Moller C, Wiklund L, Sommer W, Thorsell A, Heilig M: Decreased experimental anxiety and voluntary ethanol consumption in rats following central but not basolateral amygdala lesions. Brain Res. 1997, 760: 94-101. 10.1016/S0006-8993(97)00308-9.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.