Neurobiology of memory and anxiety: from genes to behavior

Allan V Kalueff, Allan V Kalueff

Abstract

Interaction of anxiety and memory represents an essential feature of CNS functioning. This paper reviews experimental data coming from neurogenetics, neurochemistry, and behavioral pharmacology (as well as parallel clinical findings) reflecting different mechanisms of memory-anxiety interplay, including brain neurochemistry, circuitry, pharmacology, neuroplasticity, genes, and gene-environment interactions. It emphasizes the complexity and nonlinearity of such interplay, illustrated by a survey of anxiety and learning/memory phenotypes in various genetically modified mouse models that exhibit either synergistic or reciprocal effects of the mutation on anxiety levels and memory performance. The paper also assesses the putative role of different neurotransmitter systems and neuropeptides in the regulation of memory processes and anxiety, and discusses the role of neural plasticity in these mechanisms.

Figures

Figure 1
Figure 1
Stress, memory, and anxiety interplay.

References

    1. Clement Y, Chapouthier G. Biological bases of anxiety. Neuroscience and Biobehavioral Reviews. 1998;22(5):623–633.
    1. Nutt DJ. Neurobiological mechanisms in generalized anxiety disorder. Journal of Clinical Psychiatry. 2001;62(supplement 11):22–27.
    1. Nutt DJ. Overview of diagnosis and drug treatments of anxiety disorders. CNS Spectrums. 2005;10(1):49–56.
    1. Nutt DJ, Malizia AL. New insights into the role of the GABAA-benzodiazepine receptor in psychiatric disorder. British Journal of Psychiatry. 2001;179:390–396.
    1. Nutt DJ, Ballenger JC, Sheehan D, Wittchen H-U. Generalized anxiety disorder: comorbidity, comparative biology and treatment. International Journal of Neuropsychopharmacology. 2002;5(4):315–325.
    1. Bailey KR, Rustay NR, Crawley JN. Behavioral phenotyping of transgenic and knockout mice: practical concerns and potential pitfalls. ILAR Journal. 2006;47(2):124–131.
    1. Crawley JN. Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Research. 1999;835(1):18–26.
    1. MGI Mouse Genome Informatics. 2006. .
    1. MPD Mouse Phenome Database. 2006. .
    1. Singewald N, Salchner P, Sharp T. Induction of c-Fos expression in specific areas of the fear circuitry in rat forebrain by anxiogenic drugs. Biological Psychiatry. 2003;53(4):275–283.
    1. Dagnino-Subiabre A, Orellana JA, Carmona-Fontaine C, et al. Chronic stress decreases the expression of sympathetic markers in the pineal gland and increases plasma melatonin concentration in rats. Journal of Neurochemistry. 2006;97(5):1279–1287.
    1. Kalueff AV, Nutt DJ. Role of GABA in memory and anxiety. Depression and Anxiety. 1996;4(3):100–110.
    1. Wall PM, Messier C. Concurrent modulation of anxiety and memory. Behavioural Brain Research. 2000;109(2):229–241.
    1. Yerkes RM, Dodson JD. The relation of strength of stimulus to rapidity of habit-formation. Journal of Comparative Neurology and Psychology. 1908;18(5):459–482.
    1. Barad M. Fear extinction in rodents: basic insight to clinical promise. Current Opinion in Neurobiology. 2005;15(6):710–715.
    1. Beuzen A, Belzung C. Link between emotional memory and anxiety states: a study by principal component analysis. Physiology and Behavior. 1995;58(1):111–118.
    1. Chapouthier G, Venault P. GABAA receptor complex and memory processes. Medicinal Chemistry Reviews. 2004;1(1):91–99.
    1. Gerlai R. Memory enhancement: the progress and our fears. Genes, Brain and Behavior. 2003;2(4):187–190.
    1. Parent MB, Habib MK, Baker GB. Time-dependent changes in brain monoamine oxidase activity and in brain levels of monoamines and amino acids following acute administration of the antidepressant/antipanic drug phenelzine. Biochemical Pharmacology. 2000;59(10):1253–1263.
    1. Quirk GJ, Gehlert DR. Inhibition of the amygdala: key to pathological states? Annals of the New York Academy of Sciences. 2003;985:263–272.
    1. Izquierdo I, Medina JH. GABAA receptor modulation of memory: the role of endogenous benzodiazepines. Trends in Pharmacological Sciences. 1991;12(7):260–265.
    1. Izquierdo I, Medina JH. Correlation between the pharmacology of long-term potentiation and the pharmacology of memory. Neurobiology of Learning and Memory. 1995;63(1):19–32.
    1. Bannerman DM, Rawlins JNP, McHugh SB, et al. Regional dissociations within the hippocampus—memory and anxiety. Neuroscience and Biobehavioral Reviews. 2004;28(3):273–283.
    1. Bierman EJM, Comijs HC, Jonker C, Beekman ATF. Effects of anxiety versus depression on cognition in later life. American Journal of Geriatric Psychiatry. 2005;13(8):686–693.
    1. El Hage W, Peronny S, Griebel G, Belzung C. Impaired memory following predatory stress in mice is improved by fluoxetine. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2004;28(1):123–128.
    1. El Hage W, Griebel G, Belzung C. Long-term impaired memory following predatory stress in mice. Physiology and Behavior. 2006;87(1):45–50.
    1. Ribeiro RL, Andreatini R, Wolfman C, Viola H, Medina JH, Da Cunha C. The ‘anxiety state’ and its relation with rat models of memory and habituation. Neurobiology of Learning and Memory. 1999;72(2):78–94.
    1. Savić MM, Obradović DI, Ugrešić ND, Bokonjić DR. Memory effects of benzodiazepines: memory stages and types versus binding-site subtypes. Neural Plasticity. 2005;12(4):289–298.
    1. Savić MM, Obradović DI, Ugrešić ND, Cook JM, Sarma PVVS, Bokonjić DR. Bidirectional effects of benzodiazepine binding site ligands on active avoidance acquisition and retention: differential antagonism by flumazenil and β-CCt. Psychopharmacology. 2005;180(3):455–465.
    1. Savić MM, Obradović DI, Ugrešić ND, Cook JM, Yin W, Bokonjić DR. Bidirectional effects of benzodiazepine binding site ligands in the passive avoidance task: differential antagonism by flumazenil and β-CCt. Behavioural Brain Research. 2005;158(2):293–300.
    1. Gingrich JA, Hen R. Dissecting the role of the serotonin system in neuropsychiatric disorders using knockout mice. Psychopharmacology. 2001;155(1):1–10.
    1. Monteggia LM, Barrot M, Powell CM, et al. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(29):10827–10832.
    1. Rios M, Fan G, Fekete C, et al. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. Molecular Endocrinology. 2001;15(10):1748–1757.
    1. Wehner JM, Balogh SA. Genetic studies of learning and memory in mouse models. In: Plomin R, DeFries J, Craig I, McGuffin P, editors. Behavioral Genetics in the Postgenomic Era. Washington, DC, USA: APA; 2002. pp. 103–121.
    1. Ross SA, Wong JYF, Clifford JJ, et al. Phenotypic characterization of an α4 neuronal nicotinic acetylcholine receptor subunit knock-out mouse. Journal of Neuroscience. 2000;20(17):6431–6441.
    1. Paylor R, Nguyen M, Crawley JN, Patrick J, Beaudet A, Orr-Urtreger A. α7 nicotinic receptor subunits are not necessary for hippocampal- dependent learning or sensorimotor gating: a behavioral characterization of Acra7-deficient mice. Learning and Memory. 1998;5(4-5):302–316.
    1. Picciotto MR, Zoli M, Léna C, et al. Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature. 1995;374(6517):65–67.
    1. Buhot M-C, Malleret G, Segu L. Serotonin receptors and cognitive behaviour—an update. IDrugs. 1999;2(5):426–437.
    1. Buhot M-C, Wolff M, Savova M, Malleret G, Hen R, Segu L. Protective effect of 5-HT1B receptor gene deletion on the age-related decline in spatial learning abilities in mice. Behavioural Brain Research. 2003;142(1-2):135–142.
    1. Dirks A, Pattij T, Bouwknecht JA, et al. 5-HT1B receptor knockout, but not 5-HT1A receptor knockout mice, show reduced startle reactivity and footshock-induced sensitization, as measured with the acoustic startle response. Behavioural Brain Research. 2001;118(2):169–178.
    1. López-Rubalcava C, Hen R, Cruz SL. Anxiolytic-like actions of toluene in the burying behavior and plus-maze tests: differences in sensitivity between 5-HT(1B) knockout and wild-type mice. Behavioural Brain Research. 2000;115(1):85–94.
    1. Wolff M, Savova M, Malleret G, Hen R, Segu L, Buhot M-C. Serotonin 1B knockout mice exhibit a task-dependent selective learning facilitation. Neuroscience Letters. 2003;338(1):1–4.
    1. Parks CL, Robinson PS, Sibille E, Shenk T, Toth M. Increased anxiety of mice lacking the serotonin1A receptor. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(18):10734–10739.
    1. Sarnyai Z, Sibille EL, Pavlides C, Fenster RJ, McEwen BS, Tóth M. Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin1A receptors. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(26):14731–14736.
    1. Sibille E, Pavlides C, Benke D, Toth M. Genetic inactivation of the serotonin(1A) receptor in mice results in downregulation of major GABAA receptor α subunits, reduction of GABAA receptor binding, and benzodiazepine-resistant anxiety. Journal of Neuroscience. 2000;20(8):2758–2765.
    1. Grailhe R, Waeber C, Dulawa SC, et al. Increased exploratory activity and altered response to LSD in mice lacking the 5-HT (5A) receptor. Neuron. 1999;22(3):581–591.
    1. Holmes A, Murphy DL, Crawley JN. Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biological Psychiatry. 2003;54(10):953–959.
    1. Crestani F, Keist R, Fritschy J-M, et al. Trace fear conditioning involves hippocampal α5 GABAA receptors. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(13):8980–8985.
    1. Crestani F, Lorez M, Baer K, et al. Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nature Neuroscience. 1999;2(9):833–839.
    1. Rizk A, Curley J, Robertson J, Raber J. Anxiety and cognition in histamine H3receptor−/− mice. European Journal of Neuroscience. 2004;19(7):1992–1996.
    1. Toyota H, Dugovic C, Koehl M, et al. Behavioral characterization of mice lacking histamine H3 receptors. Molecular Pharmacology. 2002;62(2):389–397.
    1. Yee BK, Balic E, Singer P, et al. Disruption of glycine transporter 1 restricted to forebrain neurons is associated with a procognitive and antipsychotic phenotypic profile. Journal of Neuroscience. 2006;26(12):3169–3181.
    1. Shimshek DR, Bus T, Kim J, et al. Enhanced odor discrimination and impaired olfactory memory by spatially controlled switch of AMPA receptors. PLoS Biology. 2005;3(11):e354.
    1. Masugi M, Yokoi M, Shigemoto R, et al. Metabotropic glutamate receptor subtype 7 ablation causes deficit in fear response and conditioned taste aversion. Journal of Neuroscience. 1999;19(3):955–963.
    1. Bannerman DM, Deacon RMJ, Brady S, et al. A comparison of GluR-A-deficient and wild-type mice on a test battery assessing sensorimotor, affective, and cognitive behaviors. Behavioral Neuroscience. 2004;118(3):643–647.
    1. Grimsby J, Toth M, Chen K, et al. Increased stress response and beta-phenylethylamine in MAOB-deficient mice. Nature Genetics. 1997;17(2):206–210.
    1. Chen K, Holschneider DP, Wu W, Rebrini I, Shih JC. A spontaneous point mutation produces monoamine oxidase A/B knock-out mice with greatly elevated monoamines and anxiety-like behavior. Journal of Biological Chemistry. 2004;279(38):39645–39652.
    1. Contarino A, Dellu F, Koob GF, et al. Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1. Brain Research. 1999;835(1):1–9.
    1. Guadaño-Ferraz A, Benavides-Piccione R, Venero C, et al. Lack of thyroid hormone receptor α1 is associated with selective alterations in behavior and hippocampal circuits. Molecular Psychiatry. 2003;8(1):30–38.
    1. Venero C, Guadaño-Ferraz A, Herrero AI, et al. Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor α1 can be ameliorated by T3 treatment. Genes and Development. 2005;19(18):2152–2163.
    1. Greco B, Carli M. Reduced attention and increased impulsivity in mice lacking NPY Y2 receptors: relation to anxiolytic-like phenotype. Behavioural Brain Research. 2006;169(2):325–334.
    1. Nishiyama H, Knöpfel T, Endo S, Itohara S. Glial protein S100B modulates long-term neuronal synaptic plasticity. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(6):4037–4042.
    1. Abeliovich A, Paylor R, Chen C, Kim JJ, Wehner JM, Tonegawa S. PKCγ mutant mice exhibit mild deficits in spatial and contextual learning. Cell. 1993;75(7):1263–1271.
    1. Bowers BJ, Collins AC, Tritto T, Wehner JM. Mice lacking PKCγ exhibit decreased anxiety. Behavior Genetics. 2000;30(2):111–121.
    1. Bontekoe CJM, McIlwain KL, Nieuwenhuizen IM, et al. Knockout mouse model for Fxr2: a model for mental retardation. Human Molecular Genetics. 2002;11(5):487–498.
    1. Müller U, Cristina N, Li Z-W, et al. Behavioral and anatomical deficits in mice homozygous for a modified β-amyloid precursor protein gene. Cell. 1994;79(5):755–765.
    1. Otto C, Martin M, Wolfer DP, Lipp H-P, Maldonado R, Schütz G. Altered emotional behavior in PACAP-type-I-receptor-deficient mice. Molecular Brain Research. 2001;92(1-2):78–84.
    1. Otto C, Kovalchuk Y, Wolfer DP, et al. Impairment of mossy fiber long-term potentiation and associative learning in pituitary adenylate cyclase activating polypeptide type I receptor-deficient mice. Journal of Neuroscience. 2001;21(15):5520–5527.
    1. Yang S, Farias M, Kapfhamer D, et al. Biochemical, molecular and behavioral phenotypes of Rab3A mutations in the mouse. to appear in Genes, Brain and Behavior.
    1. D'Adamo P, Wolfer DR, Kopp C, Tobler I, Toniolo D, Lipp H-P. Mice deficient for the synaptic vesicle protein Rab3a show impaired spatial reversal learning and increased explorative activity but none of the behavioral changes shown by mice deficient for the Rab3a regulator Gdi1. European Journal of Neuroscience. 2004;19(7):1895–1905.
    1. Rauch SL, Van Der Kolk BA, Fisler RE, et al. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Archives of General Psychiatry. 1996;53(5):380–387.
    1. Phelps EA, O'Connor KJ, Gatenby JC, Gore JC, Grillon C, Davis M. Activation of the left amygdala to a cognitive representation of fear. Nature Neuroscience. 2001;4(4):437–441.
    1. Morris JS, Friston KJ, Büchel C, et al. A neuromodulatory role for the human amygdala in processing emotional facial expressions. Brain. 1998;121(1):47–57.
    1. Killgore WDS, Yurgelun-Todd DA. Activation of the amygdala and anterior cingulate during nonconscious processing of sad versus happy faces. NeuroImage. 2004;21(4):1215–1223.
    1. Killgore WDS, Yurgelun-Todd DA. Social anxiety predicts amygdala activation in adolescents viewing fearful faces. NeuroReport. 2005;16(15):1671–1675.
    1. Bueno CH, Zangrossi H, Jr, Nogueira RL, Soares VP, Viana MB. Panicolytic-like effect induced by the stimulation of GABAA and GABAB receptors in the dorsal periaqueductal grey of rats. European Journal of Pharmacology. 2005;516(3):239–246.
    1. Bueno CH, Zangrossi H, Jr, Viana MB. The inactivation of the basolateral nucleus of the rat amygdala has an anxiolytic effect in the elevated T-maze and light/dark transition tests. Brazilian Journal of Medical and Biological Research. 2005;38(11):1697–1701.
    1. Spanis CW, Bianchin MM, Izquierdo I, McGaugh JL. Excitotoxic basolateral amygdala lesions potentiate the memory impairment effect of muscimol injected into the medial septal area. Brain Research. 1999;816(2):329–336.
    1. Mei B, Li C, Dong S, Jiang CH, Wang H, Hu Y. Distinct gene expression profiles in hippocampus and amygdala after fear conditioning. Brain Research Bulletin. 2005;67(1-2):1–12.
    1. Yilmazer-Hanke DM, Roskoden T, Zilles K, Schwegler H. Anxiety-related behavior and densities of glutamate, GABAA, acetylcholine and serotonin receptors in the amygdala of seven inbred mouse strains. Behavioural Brain Research. 2003;145(1-2):145–159.
    1. Caldji C, Diorio J, Anismam H, Meaney MJ. Maternal behavior regulates benzodiazepine/GABAA receptor subunit expression in brain regions associated with fear in BALB/c and C57BL/6 mice. Neuropsychopharmacology. 2004;29(7):1344–1352.
    1. Da Cunha C, De Stein ML, Wolfman C, Koya R, Izquierdo I, Medina JH. Effect of various training procedures on performance in an elevated plus-maze: possible relation with brain regional levels of benzodiazepine-like molecules. Pharmacology Biochemistry and Behavior. 1992;43(3):677–681.
    1. Rogan MT, Leon KS, Perez DL, Kandel ER. Distinct neural signatures for safety and danger in the amygdala and striatum of the mouse. Neuron. 2005;46(2):309–320.
    1. Stork O, Ji F-Y, Obata K. Reduction of extracellular GABA in the mouse amygdala during and following confrontation with a conditioned fear stimulus. Neuroscience Letters. 2002;327(2):138–142.
    1. Wik G, Fredrikson M, Ericson K, Eriksson L, Stone-Elander S, Greitz T. A functional cerebral response to frightening visual stimulation. Psychiatry Research - Neuroimaging. 1993;50(1):15–24.
    1. Bremner JD, Narayan M, Staib LH, Southwick SM, McGlashan T, Charney DS. Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. American Journal of Psychiatry. 1999;156(11):1787–1795.
    1. Zhang L, Rubinow DR, Ma W, et al. GABA receptor subunit mRNA expression in brain of conflict, yoked control and control rats. Molecular Brain Research. 1998;58(1-2):16–26.
    1. Kalisch R, Schubert M, Jacob W, et al. Anxiety and hippocampus volume in the rat. Neuropsychopharmacology. 2006;31(5):925–932.
    1. Zimmerberg B, Brunelli SA, Fluty AJ, Frye CA. Differences in affective behaviors and hippocampal allopregnanolone levels in adult rats of lines selectively bred for infantile vocalizations. Behavioural Brain Research. 2005;159(2):301–311.
    1. Zilles K, Wu J, Crusio WE, Schwegler H. Water maze and radial maze learning and the density of binding sites of glutamate, GABA, and serotonin receptors in the hippocampus of inbred mouse strains. Hippocampus. 2000;10(3):213–225.
    1. Hobin JA, Ji J, Maren S. Ventral hippocampal muscimol disrupts context-specific fear memory retrieval after extinction in rats. Hippocampus. 2006;16(2):174–182.
    1. Jerusalinsky D, Kornisiuk E, Izquierdo I. Cholinergic neurotransmission and synaptic plasticity concerning memory processing. Neurochemical Research. 1997;22(4):507–515.
    1. Abe Y, Aoyagi A, Hara T, et al. Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease. Journal of Pharmacological Sciences. 2003;93(1):95–105.
    1. Korpi ER, Gründer G, Lüddens H. Drug interactions at GABAA receptors. Progress in Neurobiology. 2002;67(2):113–159.
    1. Korpi ER, Sinkkonen ST. GABAA receptor subtypes as targets for neuropsychiatric drug development. Pharmacology and Therapeutics. 2006;109(1-2):12–32.
    1. Rosahl TW. Validation of GABAA receptor subtypes as potential drug targets by using genetically modified mice. Current Drug Targets. CNS and Neurological Disorders. 2003;2(4):207–212.
    1. Vicini S, Ortinski P. Genetic manipulations of GABAA receptor in mice make inhibition exciting. Pharmacology and Therapeutics. 2004;103(2):109–120.
    1. Argyropoulos SV, Nutt DJ. The use of benzodiazepines in anxiety and other disorders. European Neuropsychopharmacology. 1999;9(supplement 6):S407–S412.
    1. Lydiard RB. The role of GABA in anxiety disorders. Journal of Clinical Psychiatry. 2003;64(supplement 3):21–27.
    1. Rudolph U, Möhler H. GABA-based therapeutic approaches: GABAA receptor subtype functions. Current Opinion in Pharmacology. 2006;6(1):18–23.
    1. Sandford JJ, Argyropoulos SV, Nutt DJ. The psychobiology of anxiolytic drugs - Part 1: basic neurobiology. Pharmacology and Therapeutics. 2000;88(3):197–212.
    1. Argyropoulos SV, Sandford JJ, Nutt DJ. The psychobiology of anxiolytic drugs. Part 2: pharmacological treatments of anxiety. Pharmacology and Therapeutics. 2000;88(3):213–227.
    1. Beleboni RO, Carolino ROG, Pizzo AB, et al. Pharmacological and biochemical aspects of GABAergic neurotransmission: pathological and neuropsychobiological relationships. Cellular and Molecular Neurobiology. 2004;24(6):707–728.
    1. De-Paris F, Busnello JV, Vianna MRM, et al. The anticonvulsant compound gabapentin possesses anxiolytic but not amnesic effects in rats. Behavioural Pharmacology. 2000;11(2):169–173.
    1. Lang AP, De Angelis L. Experimental anxiety and antiepileptics: the effects of valproate and vigabatrin in the mirrored chamber test. Methods and Findings in Experimental and Clinical Pharmacology. 2003;25(4):265–271.
    1. Nemeroff CB. The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacology Bulletin. 2003;37(4):133–146.
    1. Stahl SM. Anticonvulsants as anxiolytics, part 1: tiagabine and other anticonvulsants with actions on GABA. The Journal of Clinical Psychiatry. 2004;65(3):291–292.
    1. Akirav I, Raizel H, Maroun M. Enhancement of conditioned fear extinction by infusion of the GABAA agonist muscimol into the rat prefrontal cortex and amygdala. European Journal of Neuroscience. 2006;23(3):758–764.
    1. Chhatwal JP, Myers KM, Ressler KJ, Davis M. Regulation of gephyrin and GABAA receptor binding within the amygdala after fear acquisition and extinction. Journal of Neuroscience. 2005;25(2):502–506.
    1. McCabe C, Shaw D, Atack JR, et al. Subtype-selective GABAergic drugs facilitate extinction of mouse operant behaviour. Neuropharmacology. 2004;46(2):171–178.
    1. Zarrindast MR, Bakhsha A, Rostami P, Shafaghi B. Effects of intrahippocampal injection of GABAergic drugs on memory retention of passive avoidance learning in rats. Journal of Psychopharmacology. 2002;16(4):313–319.
    1. Zarrindast M-R, Noorbakhshnia M, Motamedi F, Haeri-Rohani A, Rezayof A. Effect of the GABAergic system on memory formation and state-dependent learning induced by morphine in rats. Pharmacology. 2006;76(2):93–100.
    1. Chapouthier G, Venault P. GABAA receptor complex and memory processes. Current Topics in Medicinal Chemistry. 2002;2(8):841–851.
    1. Birzniece V, Bäckström T, Johansson I-M, et al. Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems. Brain Research Reviews. 2006;51(2):212–239.
    1. Blum S, Hebert AE, Dash PK. A role for the prefrontal cortex in recall of recent and remote memories. NeuroReport. 2006;17(3):341–344.
    1. Chandra D, Korpi ER, Miralles CP, de Blas AL, Homanics GE. GABAA receptor γ2 subunit knockdown mice have enhanced anxiety-like behavior but unaltered hypnotic response to benzodiazepines. BMC Neuroscience. 2005;6 Article ID 30, 13 pages.
    1. Marowsky A, Fritschy J-M, Vogt KE. Functional mapping of GABAA receptor subtypes in the amygdala. European Journal of Neuroscience. 2004;20(5):1281–1289.
    1. Yee BK, Hauser J, Dolgov VV, et al. GABAA receptors containing the α5 subunit mediate the trace effect in aversive and appetitive conditioning and extinction of conditioned fear. European Journal of Neuroscience. 2004;20(7):1928–1936.
    1. Wang H, Zhu YZ, Wong PT-H, et al. cDNA microarray analysis of gene expression in anxious PVG and SD rats after cat-freezing test. Experimental Brain Research. 2003;149(4):413–421.
    1. Verkuyl JM, Hemby SE, Jöels M. Chronic stress attenuates GABAergic inhibition and alters gene expression of parvocellular neurons in rat hypothalamus. European Journal of Neuroscience. 2004;20(6):1665–1673.
    1. Kosel M, Rudolph U, Wielepp P, et al. Diminished GABAA receptor-binding capacity and a DNA base substitution in a patient with treatment-resistant depression and anxiety. Neuropsychopharmacology. 2004;29(2):347–350.
    1. Sen S, Villafuerte S, Nesse R, et al. Serotonin transporter and GABAA alpha 6 receptor variants are associated with neuroticism. Biological Psychiatry. 2004;55(3):244–249.
    1. Feusner J, Ritchie T, Lawford B, Young RM, Kann B, Noble EP. GABAA receptor β3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population. Psychiatry Research. 2001;104(2):109–117.
    1. Uhart M, McCaul ME, Oswald LM, Choi L, Wand GS. GABRA6 gene polymorphism and an attenuated stress response. Molecular Psychiatry. 2004;9(11):998–1006.
    1. Maren S, Quirk GJ. Neuronal signalling of fear memory. Nature Reviews Neuroscience. 2004;5(11):844–852.
    1. Pape H-C, Stork O. Genes and mechanisms in the amygdala involved in the formation of fear memory. Annals of the New York Academy of Sciences. 2003;985:92–105.
    1. Schmitt U, Hiemke C. Tiagabine, a γ-amino-butyric acid transporter inhibitor impairs spatial learning of rats in the Morris water-maze. Behavioural Brain Research. 2002;133(2):391–394.
    1. Atack JR. Anxioselective compounds acting at the GABAA receptor benzodiazepine binding site. Current Drug Targets. CNS and Neurological Disorders. 2003;2(4):213–232.
    1. Atack JR. The benzodiazepine binding site of GABAA receptors as a target for the development of novel anxiolytics. Expert Opinion on Investigational Drugs. 2005;14(5):601–618.
    1. Atack JR, Hutson PH, Collinson N, et al. Anxiogenic properties of an inverse agonist selective for α3 subunit-containing GABAA receptors. British Journal of Pharmacology. 2005;144(3):357–366.
    1. Hu J-H, Ma Y-H, Jiang J, et al. Cognitive impairment in mice over-expressing γ-aminobutyric acid transporter 1 (GAT1) NeuroReport. 2004;15(1):9–12.
    1. Möhler H, Fritschy J-M, Crestani F, Hensch T, Rudolph U. Specific GABAA circuits in brain development and therapy. Biochemical Pharmacology. 2004;68(8):1685–1690.
    1. Bushell TJ, Sansig G, Shigemoto R, et al. An impairment of hippocampal synaptic plasticity in mice lacking mGlu7 receptors. Neuropharmacology. 1996;35(6):A6.
    1. Garpenstrand H, Annas P, Ekblom J, Oreland L, Fredrikson M. Human fear conditioning is related to dopaminergic and serotonergic biological markers. Behavioral Neuroscience. 2001;115(2):358–364.
    1. Pezze MA, Feldon J. Mesolimbic dopaminergic pathways in fear conditioning. Progress in Neurobiology. 2004;74(5):301–320.
    1. Bolivar V, Flaherty L. A region on chromosome 15 controls intersession habituation in mice. Journal of Neuroscience. 2003;23(28):9435–9438.
    1. Gallinat J, Ströhle A, Lang UE, et al. Association of human hippocampal neurochemistry, serotonin transporter genetic variation, and anxiety. NeuroImage. 2005;26(1):123–131.
    1. Maron E, Nikopensius T, Kõks S, et al. Association study of 90 candidate gene polymorphisms in panic disorder. Psychiatric Genetics. 2005;15(1):17–24.
    1. Graeff FG, Silveira MC, Nogueira RL, Audi EA, Oliveira RMW. Role of the amygdala and periaqueductal gray in anxiety and panic. Behavioural Brain Research. 1993;58(1-2):123–131.
    1. Groenink L, Van Bogaert MJV, Van Der Gugten J, Oosting RS, Olivier B. 5-HT1A receptor and 5-HT1b receptor knockout mice in stress and anxiety paradigms. Behavioural Pharmacology. 2003;14(5-6):369–383.
    1. Hensler JG. Serotonergic modulation of the limbic system. Neuroscience and Biobehavioral Reviews. 2006;30(2):203–214.
    1. Kusserow H, Davies B, Hörtnagl H, et al. Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin1A receptors. Molecular Brain Research. 2004;129(1-2):104–116.
    1. Lesch KP. Neurotism and serotonin: a developmental genetic perspective. In: Plomin R, DeFries J, Craig I, McGuffin P, editors. Behavioral Genetics in the Postgenomic Era. Washington, DC, USA: American Psychological Association; 2002. pp. 389–423.
    1. Lesch KP, Zeng Y, Reif A, Gutknecht L. Anxiety-related traits in mice with modified genes of the serotonergic pathway. European Journal of Pharmacology. 2003;480(1–3):185–204.
    1. Murphy DL, Lerner A, Rudnick G, Lesch K-P. Serotonin transporter: gene, genetic disorders, and pharmacogenetics. Molecular Interventions. 2004;4(2):109–123.
    1. Holmes A, Yang RJ, Lesch K-P, Crawley JN, Murphy DL. Mice lacking the serotonin transporter exhibit 5-HT1A receptor-mediated abnormalities in tests for anxiety-like behavior. Neuropsychopharmacology. 2003;28(12):2077–2088.
    1. Murphy DL, Uhl GR, Holmes A, et al. Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders. Genes, Brain and Behavior. 2003;2(6):350–364.
    1. Zhao S, Edwards J, Carroll J, et al. Insertion mutation at the C-terminus of the serotonin transporter disrupts brain serotonin function and emotion-related behaviors in mice. Neuroscience. 2006;140(1):321–334.
    1. Adamec R, Burton P, Blundell J, Murphy DL, Holmes A. Vulnerability to mild predator stress in serotonin transporter knockout mice. Behavioural Brain Research. 2006;170(1):126–140.
    1. Zhang S, Amstein T, Shen J, Brush FR, Gershenfeld HK. Molecular correlates of emotional learning using genetically selected rat lines. Genes, Brain and Behavior. 2005;4(2):99–109.
    1. Mizuno T, Aoki M, Shimada Y, et al. Gender difference in association between polymorphism of serotonin transporter gene regulatory region and anxiety. Journal of Psychosomatic Research. 2006;60(1):91–97.
    1. Bertolino A, Arciero G, Rubino V, et al. Variation of human amygdala response during threatening stimuli as a function of 5′HTTLPR genotype and personality style. Biological Psychiatry. 2005;57(12):1517–1525.
    1. Hariri AR, Drabant EM, Weinberger DR. Imaging genetics: perspectives from studies of genetically driven variation in serotonin function and corticolimbic affective processing. Biological Psychiatry. 2006;59(10):888–897.
    1. Stein DJ, Matsunaga H. Specific phobia: a disorder of fear conditioning and extinction. CNS Spectrums. 2006;11(4):248–251.
    1. Payton A, Gibbons L, Davidson Y, et al. Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population. Molecular Psychiatry. 2005;10(12):1133–1139.
    1. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003;301(5631):386–389.
    1. Fox NA, Nichols KE, Henderson HA, et al. Evidence for a gene-environment interaction in predicting behavioral inhibition in middle childhood. Psychological Science. 2005;16(12):921–926.
    1. Kalueff AV, Avgustinovich DF, Kudryavtseva NN, Murphy DL. BDNF in anxiety and depression. Science. 2006;312(5780):1598–1599.
    1. Linnarsson S, Björklund A, Ernfors P. Learning deficit in BDNF mutant mice. European Journal of Neuroscience. 1997;9(12):2581–2587.
    1. Chourbaji S, Hellweg R, Brandis D, et al. Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior. Molecular Brain Research. 2004;121(1-2):28–36.
    1. Montkowski A, Holsboer F. Intact spatial learning and memory in transgenic mice with reduced BDNF. NeuroReport. 1997;8(3):779–782.
    1. Berton O, McClung CA, DiLeone RJ, et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006;311(5762):864–868.
    1. Cirulli F, Berry A, Chiarotti F, Alleva E. Intrahippocampal administration of BDNF in adult rats affects short-term behavioral plasticity in the Morris water maze and performance in the elevated plus-maze. Hippocampus. 2004;14(7):802–807.
    1. Alonso M, Bekinschtein P, Cammarota M, Vianna MRM, Izquierdo I, Medina JH. Endogenous BDNF is required for long-term memory formation in the rat parietal cortex. Learning and Memory. 2005;12(5):504–510.
    1. Koponen E, Võikar V, Riekki R, et al. Transgenic mice overexpressing the full-length neurotrophin receptor trkB exhibit increased activation of the trkB-PLCγ pathway, reduced anxiety, and facilitated learning. Molecular and Cellular Neuroscience. 2004;26(1):166–181.
    1. Gorski JA, Balogh SA, Wehner JM, Jones KR. Learning deficits in forebrain-restricted brain-derived neurotrophic factor mutant mice. Neuroscience. 2003;121(2):341–354.
    1. Schulkin J, Morgan MA, Rosen JB. A neuroendocrine mechanism for sustaining fear. Trends in Neurosciences. 2005;28(12):629–635.
    1. Rainnie DG, Bergeron R, Sajdyk TJ, Patil M, Gehlert DR, Shekhar A. Corticotrophin releasing factor-induced synaptic plasticity in the amygdala translates stress into emotional disorders. Journal of Neuroscience. 2004;24(14):3471–3479.
    1. Shekhar A, Truitt W, Rainnie D, Sajdyk T. Role of stress, corticotrophin releasing factor (CRF) and amygdala plasticity in chronic anxiety. Stress. 2005;8(4):209–219.
    1. Kojro E, Postina R, Buro C, Meiringer C, Gehrig-Burger K, Fahrenholz F. The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein. FASEB Journal. 2006;20(3):512–514.
    1. Kapfhamer D, Valladares O, Sun Y, et al. Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse. Nature Genetics. 2002;32(2):290–295.
    1. Thakker-Varia S, Alder J, Crozier RA, Plummer MR, Black IB. Rab3A is required for brain-derived neurotrophic factor-induced synaptic plasticity: transcriptional analysis at the population and single-cell levels. Journal of Neuroscience. 2001;21(17):6782–6790.
    1. Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors. 2004;22(3):123–131.
    1. Francia N, Cirulli F, Chiarotti F, Antonelli A, Aloe L, Alleva E. Spatial memory deficits in middle-aged mice correlate with lower exploratory activity and a subordinate status: role of hippocampal neurotrophins. European Journal of Neuroscience. 2006;23(3):711–728.
    1. Song L, Che W, Min-Wei W, Murakami Y, Matsumoto K. Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress. Pharmacology Biochemistry and Behavior. 2006;83(2):186–193.
    1. Rattiner LM, Davis M, Ressler KJ. Differential regulation of brain-derived neurotrophic factor transcripts during the consolidation of fear learning. Learning and Memory. 2004;11(6):727–731.
    1. Rattiner LM, Davis M, Ressler KJ. Brain-derived neurotrophic factor in amygdala-dependent learning. Neuroscientist. 2005;11(4):323–333.
    1. Lang UE, Hellweg R, Kalus P, et al. Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology. 2005;180(1):95–99.
    1. Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta J-K. BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biological Psychiatry. 2006;59(9):812–815.
    1. Dempster E, Toulopoulou T, McDonald C, et al. Association between BDNF val66 met genotype and episodic memory. American Journal of Medical Genetics. 2005;134 B(1):73–75.
    1. Mattson MP, Maudsley S, Martin B. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends in Neurosciences. 2004;27(10):589–594.
    1. Rios M, Lambe EK, Liu R, et al. Severe deficits in 5-HT2A-mediated neurotransmission in BDNF conditional mutant mice. Journal of Neurobiology. 2006;66(4):408–420.
    1. Siuciak JA, Boylan C, Fritsche M, Altar CA, Lindsay RM. BDNF increases monoaminergic activity in rat brain following intracerebroventricular or intraparenchymal administration. Brain Research. 1996;710(1-2):11–20.
    1. Szapacs ME, Mathews TA, Tessarollo L, Ernest Lyons W, Mamounas LA, Andrews AM. Exploring the relationship between serotonin and brain-derived neurotrophic factor: analysis of BDNF protein and extraneuronal 5-HT in mice with reduced serotonin transporter or BDNF expression. Journal of Neuroscience Methods. 2004;140(1-2):81–92.
    1. Payton A. Investigating cognitive genetics and its implications for the treatment of cognitive deficit. Genes, Brain and Behavior. 2006;5(supplement 1):44–53.
    1. Ren-Patterson RF, Cochran LW, Holmes A, et al. Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. Journal of Neuroscience Research. 2005;79(6):756–771.
    1. Kaufman J, Yang B-Z, Douglas-Palumberi H, et al. Social supports and serotonin transporter gene moderate depression in maltreated children. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(49):17316–17321.

Source: PubMed

3
Se inscrever